Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin).

BACKGROUND AND PURPOSE: The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. METHODS: STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of ≤2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. RESULTS: From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35-2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). CONCLUSIONS: Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01073007.

Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study.

BACKGROUND: Variants in the 5-lipoxygenase-activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) genes have first been associated with ischemic stroke (IS) through whole-genome linkage screens. However, association studies obtained conflicting results. We aimed to investigate the contribution of selected single nucleotide polymorphisms (SNPs) in these genes for the first time in a large Iberian population. METHODS: A case-control design was used to analyze one SNP in ALOX5AP and five SNPs in PDE4D in a total of 1,092 IS patients and 781 healthy controls of two different subsets from Spain and Portugal. The analysis was adjusted for confounding variables and the results were integrated in a meta-analysis of all case-control studies. In addition, ALOX5AP gene expression levels were determined in controls and IS cases. RESULTS: A first meta-analysis of both subsets showed that the T allele of the SG13S114 SNP in ALOX5AP was a risk factor for IS after Bonferroni correction [OR = 1.22 (1.06-1.40); p = 0.006]. A second meta-analysis of white populations confirmed these results [OR = 1.18 (1.07-1.31); p = 0.001]. ALOX5AP gene expression analysis in a subset of controls and cases revealed that the SG13S114 genotypes modulate mRNA levels of ALOX5AP (p = 0.001) and mRNA levels were higher in IS cases (2.8 +/- 2.4%) than in controls (1.4 +/- 1.3%; p = 0.003). No association of the variants in PDE4D with IS was observed in our study. CONCLUSIONS: The ALOX5AP SG13S114 variant is an independent risk factor for IS in the Iberian population and is associated with ALOX5AP expression levels. The role of this gene in stroke merits further investigation.

Oxidative stress after thrombolysis-induced reperfusion in human stroke.

BACKGROUND AND PURPOSE: Animal models of transient ischemia suggest that oxygen-derived free radicals produced on reperfusion of ischemic brain could constitute the main cause of reperfusion injury. We aimed to determine the presence and role of lipid peroxidation and protein oxidation-related molecules after tissue plasminogen activator-induced recanalization in human stroke. METHODS: A total of 160 patients with strokes involving the middle cerebral artery and treated with tissue plasminogen activator and 60 healthy controls were included. Blood samples, transcranial Doppler recordings, and National Institutes of Health Stroke Scale scores were obtained at baseline (pretreatment), 1 hour and 2 hours after tissue plasminogen activator bolus, and 12 hours and 24 hours after stroke onset. The main lipid peroxidation end-product malondialdehyde, advanced oxidation protein products, and plasma concentrations of myeloperoxidase were assessed. RESULTS: At baseline, all oxidative stress biomarkers were higher than in control subjects (P<0.01 for all comparisons). Malondialdehyde remained high compared with controls during the study period, whereas myeloperoxidase concentrations were significantly raised at baseline, 1 hour after tissue plasminogen activator administration, and 12 hours after stroke onset. Malondialdehyde concentrations correlated with stroke severity and were associated with outcome and with hemorrhagic complications. Regarding recanalization, among those patients with middle cerebral artery recanalization by the end of tissue plasminogen activator infusion (44%) or anytime thereafter, no peaking of any of the studied molecules could be identified. CONCLUSIONS: Our study showed that systemic oxidative damage to lipids and proteins had already occurred at baseline in stroke. In contrast to animal studies, a relationship between free radical-mediated oxidative damage to lipids or proteins and reperfusion injury after arterial recanalization could not be established.

KCNK17 genetic variants in ischemic stroke.

BACKGROUND: Genetic factors contribute to the development of ischemic stroke (IS). In order to identify susceptibility variants, we analyzed single nucleotide polymorphisms (SNPs) that had been previously linked to stroke in a genome-wide association study. METHODS: We analyzed 12 SNPs in a White population comprising IS patients and healthy controls. The analysis was adjusted for confounding variables and stratified by stroke etiology. Functional studies were then performed to elucidate the role of these variants in IS. RESULTS: In a preliminary analysis of 268 controls and 531 IS cases, the rs10947803 SNP of KCNK17 (p=0.012) and the rs7506045 of IMPA2 (p=0.040) were associated with IS, although only the KCNK17 gene was an independent risk factor for IS. In a second phase, analysis of 271 new IS cases revealed that the A allele of rs10947803 was associated with stroke after correction for Bonferroni (OR=1.48; 95% CI, 1.14-1.91, p=0.003). Gene expression analysis revealed that KCNK17 mRNA levels were higher in the IS cases in the acute phase than in controls (14+/-78% vs. 91+/-41, p=0.002) but not in the chronic phase (56+/-57%; p=0.230). Moreover, RNA levels depended on the alleles of the rs10947803 SNP in the control group (p=0.021) and in the chronic phase (p=0.033). CONCLUSIONS: The A allele of the rs10947803 variant of KCNK17 was associated with increased risk of IS and increased levels of KCNK17 gene expression. The role of this potassium channel gene in IS opens diagnostic and therapeutic expectations and merits further investigation.

Lower concentrations of thrombin-antithrombin complex (TAT) correlate to higher recanalisation rates among ischaemic stroke patients treated with t-PA.

An elevated concentration of the thrombin-antithrombin complex (TAT) has been associated with high mortality rates and poor outcome in ischaemic stroke patients treated with tissue plasminogen activator (t-PA). Moreover, antithrombin drugs have been tested in combination with t-PA in the acute phase of ischaemic stroke to increase treatment efficacy. We aimed to study whether poor outcome associated with TAT among ischaemic stroke patients treated with t-PA could be due to the effects of this complex on recanalisation rates of the middle cerebral artery (MCA) and on haemorrhagic transformation. The TAT levels of 89 patients having a proximal MCA occlusion were measured by ELISA, and the patients were then treated with t-PA. Complete recanalisation was diagnosed by transcranial Doppler (TCD) at 1, 2 and 6 hours post-t-PA infusion and haemorrhagic transformation was identified by computed tomography (CT). Lower levels of TAT were associated with better recanalisation rates at all time-points (1 hour: OR = 24.8 95% CI 1.4-434.8, p = 0.028; 2 hours: OR = 6.3 95% CI 1.5-27, p = 0.014; 6 hours: OR = 6.4 95% CI 1.5-26.5, p = 0.011) after adjustment for stroke risk factors. However, no correlation was found between TAT concentration and haemorrhagic transformation. The elevated mortality rates previously observed in patients with high levels of TAT might have been due to revascularisation resistance. Low levels of TAT are not associated with an increase in haemorrhagic complications after t-PA, indicating that the combination of thrombin blockers and t-PA could be a safe and effective treatment for ischaemic stroke in the future.