Although the dose of pravastatin

Although the dose of pravastatin (10mg/day) was lower than used in studies from the Western countries (Shepherd et al., 2002; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002), it was the approved standard dose in Japan. Indeed, the levels of total cholesterol and LDL cholesterol were substantially reduced and kept in the normal ranges in the pravastatin group (Fig. 2A,B). Also, level of HDL cholesterol was slightly higher in the pravastatin group (Fig. 2D), which could have exerted favorable impact on jnk pathway in this group of patients (Kuwashiro et al., 2012; Nishimura et al., 2013). As a well-defined stroke risk factor, blood pressure level was similarly well controlled in both groups (Fig. 2E,F), making it unlikely that the level exerted significant influence on the recurrence of stroke in either group. Given the nature of study sample, incidence of recurrent stroke (approximately 2.6%/year in both groups) was roughly half of our initial assumption, but turned out to be similar to the recent report from Japan (Shinohara et al., 2010). As the primary endpoint, although total stroke recurrence was similar between the two groups, patient accrual was insufficient and statistical power was not enough, requiring further studies to adequately address to the intergroup difference. However, even under such conditions, onset of atherothrombotic infarction was clearly less frequent in pravastatin group, whereas no significant difference was found for other stroke subtypes (Fig. 3). This finding may be reasonable, if pravastatin exerted atheroprotective effects on the carotid and major cerebral arteries (Crisby et al., 2001; Byington et al., 1995; Crouse et al., 2007), thus suppressing the progression of underlying atherosclerotic processes. However, how levels of LDL cholesterol or other pleiotropic effects have contributed to the risk reduction cannot be determined from this study. Of note, reduction of LDL cholesterol was roughly 20% in this study, compared to the baseline (Fig. 2B), which may not be an effective reduction for stroke prevention (Boekholdt et al., 2014; Corvol et al., 2003; Amarenco et al., 2004). On the other hand, many studies have suggested pleiotropic effects of statins, including atheromatous plaque stabilization and anti-inflammation (Crisby et al., 2001; Byington et al., 1995; Crouse et al., 2007; Tsuda et al., 1996; Ridker et al., 1999; Albert et al., 2001; Uchiyama et al., 2009), which could have played a role for the suppression of atherothrombotic infarction as found in this study. Concurrent with this study, sub-studies focusing on chronic inflammation (NCT00361699) and carotid atherosclerosis (NCT00361530) were conducted, the results of which would allow for additional elucidation on the relationship between stroke recurrence and statin use. Additionally, incidence of lacunar infarction was similar between the two groups, or tended to be even higher (not significant) in the pravastatin group (Fig. 3C). On the basis of this finding, pravastatin is not likely to suppress the stroke of small arterial pathologies, as generally referred to “small vessel disease.” However, stroke patients often have underlying cardiovascular complications and risk factors, for which utility of statin treatments should not be undervalued. Of note, although statin treatment could increase the risk of intracranial hemorrhage (Amarenco et al., 2006; Boekholdt et al., 2014), the occurrence was virtually the same between two groups (Fig. 3E). In a meta-analysis by Boekholdt et al., the risk for intracranial hemorrhage was higher in patients with very low LDL cholesterol level (<1.94mmol/L) than in patients with moderately low LDL cholesterol level (2.58 to 3.23mmol/L) (Boekholdt et al., 2014). In the current study, LDL cholesterol level in the pravastatin group was only “moderately low” (2.67mmol/L, Fig. 2B), and was substantially higher than in SPARCL trial (1.89mmol/L) in which risk of hemorrhagic stroke was increased (Amarenco et al., 2006).