Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke

ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)

Shinichi Yoshimura, MD, PhD; Kazutaka Uchida, MD; Takashi Daimon, PhD; Ryuzo Takashima, BA; Kazuhiro Kimura, PhD; Takeshi Morimoto, MD, PhD, MPH

Disclosures

Stroke. 2017;48(11):3057-3063.

Abstract and Introduction

Abstract

Background and Purpose: Several studies suggested that statins during hospitalization were associated with better disability outcomes in patients with acute ischemic stroke, but only 1 small randomized trial is available.

Methods: We conducted a multicenter, open-label, randomized controlled trial in patients with acute ischemic strokes in 11 hospitals in Japan. Patients with acute ischemic stroke and dyslipidemia randomly received statins within 24 hours after admission in the early group or on the seventh day in the delayed group, in a 1:1 ratio. Statins were administered for 12 weeks. The primary outcome was patient disability assessed by modified Rankin Scale at 90 days.

Results: A total of 257 patients were randomized and analyzed (early 131, delayed 126). At 90 days, modified Rankin Scale score distribution did not differ between groups (P=0.68), and the adjusted common odds ratio of the early statin group was 0.84 (95% confidence interval, 0.53–1.3; P=0.46) compared with the delayed statin group. There were 3 deaths at 90 days (2 in the early group, 1 in the delayed group) because of malignancy. Ischemic stroke recurred in 9 patients (6.9%) in the early group and 5 patients (4.0%) in the delayed group. The safety profile was similar between groups.

Conclusions: Our randomized trial involving patients with acute ischemic stroke and dyslipidemia did not show any superiority of early statin therapy within 24 hours of admission compared with delayed statin therapy 7 days after admission to alleviate the degree of disability at 90 days after onset.

Introduction

To improve survival and ameliorate disability after ischemic stroke, many treatment modalities have been used in the acute stage of stroke. Among them, intravenous tPA (tissue-type plasminogen activator) therapy and immediate endovascular thrombectomy have improved clinical outcomes, especially in patients with severe acute ischemic stroke.^[1,2]

Several observational studies showed that the administration of statins before ischemic stroke onset was associated with less physical disability^[3] and that statin administration during hospitalization was associated with better survival and disability outcomes.^[4–7] However, 1 small randomized controlled trial (RCT) failed to show the benefit of statin use at the acute phase of ischemic stroke for significantly decreased disability.^[8] A recent meta-analysis proposed the necessity of an RCT to determine the usefulness of statin therapy for acute ischemic stroke.^[9]

Thus, we conducted a multicenter RCT to determine the relative efficacy of early versus delayed statin treatment in patients with acute ischemic stroke. We hypothesized that early statin treatment would be associated with significantly improved physical disability at 90 days after acute ischemic stroke.

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References
Appendix

Table 1. Patients' Characteristics
Variables	Early Statin Group (n=131)	Delayed Statin Group (n=126)
Age, y, mean (SD)	70 (13)	70 (11)
Age ≥70 y, n (%)	76 (58)	68 (54)
Sex male, n (%)	86 (66)	81 (64)
History of smoking, n (%)	69 (53)	70 (56)
History of hypertension, n (%)	103 (79)	93 (74)
History of diabetes mellitus, n (%)	38 (29)	44 (35)
History of dyslipidemia, n (%)	64 (49)	59 (47)
History of stroke, n (%)	41 (31)	48 (38)
Statin use before admission, n (%)	23 (18)	16 (13)
Systolic blood pressure, mm Hg, mean (SD)	160 (24)	160 (26)
Diastolic blood pressure, mm Hg, mean (SD)	87 (15)	89 (16)
Body weight, kg, mean (SD)	64 (14)	63 (13)
NIHSS on admission, median (IQR)	3 (1–5)	3 (1–5)
Stroke classification
Lacunar, n (%)	56 (43)	56 (44)
Atherothrombotic, n (%)	55 (42)	54 (43)
Cardioembolic, n (%)	5 (4)	9 (7)
Others*, n (%)	15 (11)	7 (6)
Intravenous thrombolysis, n (%)	11 (8.4)	10 (7.9)
ASPECTS, median (IQR)	9 (9–10)	9 (9–10)
ASPECTS on DWI, median (IQR)	9 (8–9)	9 (9–9)
pc-ASPECTS on DWI, median (IQR)	8 (8–9)	8 (8–9)
Laboratories
LDL cholesterol, mmol/L, mean (SD); [mg/dL, mean (SD)]	3.52 (0.78); [136 (30)]	3.52 (0.85); [136 (33)]
HDL cholesterol, mmol/L, mean (SD); [mg/dL, mean (SD)]	1.37 (0.36); [53 (14)]	1.32 (0.44); [51 (17)]
Total cholesterol, mmol/L, mean (SD); [mg/dL, mean (SD)]	5.54 (0.91); [214 (35)]	5.44 (0.93); [210 (36)]
Triglycerides, mmol/L, median (IQR); [mg/dL, median (IQR)]	3.16 (2.07–4.09); [122 (80–158)]	3.11 (2.23–4.56); [120 (86–176)]
HbA1c, % (NGSP), median (IQR)	6.0 (5.6–6.6)	6.0 (5.6–7.0)
CRP, mg/dL, median (IQR)	0.11 (0.05–0.28)	0.11 (0.05–0.29)

ASPECTS indicates Alberta Stroke Program Early CT Score; CRP, C-reactive protein; DWI, diffusion-weighted imaging; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; NGSP, National Glycohemoglobin Standardization Program; NIHSS, National Institute of Health Stroke Scale; and pc-ASPECTS, posterior circulation-Alberta Stroke Program Early CT Score.
*Abnormality of coagulation, arterial dissection, vasculitis, or undetermined.

Table 2. Secondary Outcomes
Secondary Outcomes	Early Statin Group (n=131)	Delayed Statin Group (n=126)	P Values
Change in NIHSS from baseline through seventh day, median (IQR)	−1 (−2 to 0)	−1 (−2 to 0)	0.40
Change in LDL-C from baseline through 21st day or discharge, mmol/L, mean (SD); [mg/dL, mean (SD)]	−1.68 (0.79); [−65.0 (30.6)]	−1.32 (0.76); [−51.0 (29.2)]	0.001
Acute myocardial infarction, n (%)	0 (0)	1 (0.8)	0.49
Unstable angina, n (%)	0 (0)	0 (0)	1
New acute ischemic stroke, n (%)	9 (6.9)	5 (4.0)	0.41
Nontraumatic cerebral hemorrhage, n (%)	1 (0.7)	0 (0)	1
Nontraumatic subarachnoid hemorrhage, n (%)	1 (0.7)	0 (0)	1
Large vessel or peripheral artery disease requiring treatment, n (%)	0 (0)	1 (0.8)	0.49

IQR indicates interquartile range; LDL-C, low-density lipoprotein cholesterol; and NIHSS, National Institutes of Health Stroke Scale.

Table 3. Safety Outcomes
Outcomes	Early Statin Group (n=134)	Delayed Statin Group (n=129)
Death*	2 (1.5)	1 (0.8)
Any adverse event, n (%)	32 (23.9)	22 (17.1)
Progression of symptom†, n (%)	15 (11.2)	10 (8.5)
Musculoskeletal adverse events‡, n (%)	4 (3.0)	2 (1.6)
Liver dysfunction, n (%)	3 (2.2)	1 (0.8)
Gastrointestinal symptoms, n (%)	4 (3.0)	2 (1.6)
Renal dysfunction, n (%)	1 (0.7)	1 (0.8)
Incidental malignancy, n (%)	4 (3.0)	2 (1.6)
Incidental infection, n (%)	7 (5.2)	4 (3.1)
Incidental bleeding, n (%)	3 (2.2)	2 (1.6)
Eczema or skin lesion, n (%)	2 (1.5)	3 (2.3)
Metal disorders, n (%)	2 (1.5)	1 (0.8)
Others§, n (%)	2 (1.5)	3 (2.3)
Laboratory changes
CK ≥3×ULN, n (%)	11 (9.5)	20 (17.5)
AST ≥3×ULN, n (%)	0 (0)	1 (0.8)
ALT ≥3×ULN, n (%)	2 (1.7)	1 (0.8)

ALT indicates alanine aminotransferase; AST, aspartate transaminase; CK, creatine kinase; and ULN, upper limit of normal range.
*Gallbladder cancer, pancreatic cancer, and gastric cancer.
†Clinically worsened stroke or deterioration of NIHSS score of ≥4 points.
‡Low back pain, lower extremity myalgia, ankle sprain, knee arthrosis, and shoulder subluxation.
§Asthma, left atrial myxoma, dehydration, hypokalemia, and hypertrophic obstructive cardiomyopathy.