Table 6.
Randomized clinical trials in ischemic stroke.
| Study | Year | Treatment | Sample Size | Outcome |
|---|---|---|---|---|
| IL-1Ra | ||||
| Emsley et al. [283] | 2005 | Within 6 h of the stroke onset, patients were randomized to rhIL-1ra (intravenously by a 100 mg loading dose over 60 s, followed by a 2 mg/kg/h infusion over 72 h.) or placebo. | 34 patients (17 rhIL-1Ra, 17 placebo) | Peripheral total white blood cell and neutrophil count, CRP, and IL-6 and neutrophil counts were lower in the rhIL-1ra-treated were lower in the treated group. The drug was safe and well tolerated. |
| Smith et al. [294] | 2012 | Blood samples prior to treatment initiation, at 24 h and 5 to 7 days. LPS stimulation was made to assess cytokine production by leukocytes. | 34 patients (17 rhIL-1Ra, 17 placebo) | Induction of TNF-α (p < 0.001), IL-1β (p < 0.005), IL-6, IL-8, and IL-10 (p < 0.02) by LPS was reduced in patients at admission. At 24 h, for patients treated with IL-1Ra, induction of TNF-α, IL-6 and IL-10 was greater than in the placebo group (p < 0.05). At 5 to 7 day, TNF-α and IL-1β induction remained suppressed only in the placebo group (p < 0.05). Plasma cortisol concentrations were elevated at admission in patients compared to controls but decreased at 24 h in treated patients (p < 0.05) and inversely correlated (p < 0.001) with either TNF-α or IL-1β induction at admission. |
| Statins | ||||
| Scandinavian Simvastatin Survival Study (4S) [277] | 1994 | Patients with angina pectoris or previous MI and serum cholesterol 5.5–8.0 mmol/L on a lipid-lowering diet were randomized to double-blind treatment with simvastatin or placebo. | 4444 patients (2221 simvastatin, 2223 placebo) | Over 5.4 years, simvastatin improved lipid profile, with few adverse effects. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58–0.85, p = 0.0003). In a post hoc analysis, simvastatin was demonstrated to reduce by 30% the rate of strokes and transient ischemic attacks. |
| Plehn et al. [290] | 1999 | Enrolled patients: 21–75 years old who had experienced a myocardial infarction within the past 3 to 20 months, total cholesterol <240 mg/dL, LDL cholesterol between 115 and 174 mg/dL, and fasting triglycerides <350 mg/dL during 4 weeks of treatment. | 4159 patients (2081 pravastatin 40 mg daily and 2078 placebo) | Compared with placebo, pravastatin lowered total and LDL cholesterol, and triglycerides by 20%, 32%, and 14%, respectively. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4%–52%, p = 0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4%–44%, p = 0.02). No increase in hemorrhagic stroke with pravastatin was found. |
| Montaner et al. [288] | 2008 | Simvastatin (40 mg/day for the first week followed by a dose of 20 mg/day until day 90) or placebo were given at 3–12 h from symptom onset. | 60 patients (30 simvastatin, 30 placebo) | Simvastatin-treated group presented greater improvements at several time points (p = 0.01). Simvastatin treatment and low temperatures were the only independent predictors of a great improvement by day 90 (OR 10.3, CI 2.05–52.2, p = 0.005 and OR 0.13, CI 0.02–0.70, p = 0.017, respectively). |
| Sever et al. [292] | 2003 | Hypertensive patients aged 40–79 years with at least 3 other cardiovascular risk factors. | 10305 (5168 atorvastatin 10 mg daily and 5137 placebo) | Treatment was stopped after a median follow-up of 3.3 years. In the atorvastatin group, less primary events occurred (HR 0.64, 95% CI 0.50–0.83, p = 0.0005), especially in the first year of follow-up. Fatal and non-fatal stroke (p = 0.024), total cardiovascular events and total coronary events (p = 0.0005) were also lowered. |
| Amarenco et al. [278] | 2006 | Patients with previous stroke or TIA within one to six months, LDL cholesterol levels of 100 to 190 mg/dL, and no known coronary heart disease. | 4731 patients (2365 atorvastatin 80 mg daily and 2366 placebo) | During 4.9 years, 265 patients under atorvastatin and 311 under placebo had a fatal or non-fatal stroke (5-year absolute reduction in risk, 2.2%; adjusted HR 0.84, 95% CI, 0.71–0.99, p = 0.03; unadjusted p = 0.05). The 5-year absolute reduction in the risk of major cardiovascular events was 3.5% (HR, 0.80, 95% CI, 0.69–0.92, p = 0.002). No difference in mortality rate was seen. |
| Shepherd et al. [293] | 2002 | Patients aged 70–82 years with a history of or risk factors for vascular disease. | 5804 patients (2891 pravastatin 40 mg daily and 2913 placebo) | Pravastatin lowered LDL cholesterol and reduced the incidence of the primary endpoint (HR 0.85, 95% CI 0.74–0.97, p = 0.014). Coronary heart disease death and non-fatal MI risk was also reduced (p = 0.006). Stroke risk was unaffected (p = 0.8) as well as for TIA (p = 0.051). New cancer diagnosis were more frequent in pravastatin group (p = 0.020). Mortality from coronary heart disease was lower in the pravastatin group (p = 0.043). No significant effect on cognitive function or disability was found. |
| Ridker et al. [291] | 2008 | Apparently healthy men and women with LDL cholesterol levels of less than 130 mg/dL and hs-CRP levels of 2.0 mg/L or higher. | 17802 patients (8901 rosuvastatin 20 mg daily and 8901 placebo) | Rosuvastatin reduced LDL cholesterol levels and hs-CRP levels. Rates of occurrence of the combined primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes) were 0.77 for rosuvastatin (HR 0.56, 95% CI: 0.46–0.69, p < 0.00001; HR for stroke 0.52, 95% CI 0.34–0.79, p = 0.002). |
| Donepezil | ||||
| Barrett et al. [280] | 2011 | Adults with ischemic stroke treated within 24 h after onset of symptoms. | 33 patients receiving donepezil 5 mg daily for 30 days followed by an increase to 10 mg/day for 60 days | 15 participants had a favorable clinical outcome (NIHSS score ≤1 at day 90) (p < 0.001). |
| Cyclosporine A | ||||
| Nighoghossian et al. [289] | 2015 | Patients aged 18–85 years with an anterior-circulation stroke and eligible for thrombolytic therapy and evaluation of infarct volume on MRI at 30 days. | 127 patients (61 CsA 2 mg/kg and 66 saline) | The reduction of infarct volume in CsA-treated patients was not significant (p = 0.18). In patients with proximal occlusion and effective recanalization, infarct volume decreased in CsA-treated group (p = 0.009). |
| Edaravone | ||||
| Edaravone Acute Infarction Study Group [282] | 2003 | Patients with acute ischemic stroke within 72 h from symptom onset. | 250 patients (125 edaravone 30 mg twice a day for 14 days and 125 placebo) | A significant improvement in functional outcome evaluated by the mRS was observed in the edaravone group (p = 0.039). |
| Kaste et al. [284] | 2013 | Patients with acute ischemic stroke within 24 h from stroke onset. | 36 patients (12 edaravone with loading dose 0.08 mg/kg + 0.2 mg/kg/h; 13 edaravone loading dose 0.16 mg/kg + 0.4 mg/kg/h; 11 placebo) | Both doses of the new formulation and dosing regimen were well tolerated and showed clinical improvement based on NIHSS score. |
| Takenaka et al. [295] | 2014 | Patients admitted to hospital for cerebral infarction within 3 h after the onset of infarction. | 48 patients (20 edaravone before rt-PA and 28 edaravone and rt-PA simultaneously) | NIHSS before rt-PA showed a statistically significant improvement after rt-PA administration (p < 0.001). The mRS at 90 days also improved. |
rhIL-1Ra: recombinant human IL-1 receptor antagonist. LPS: lipopolysaccharide. TNF-α: tumor necrosis factor-α. IL: interleukin. MI: myocardial infarction. LDL: low density lipoprotein. TIA: transient ischemic attack. CI: confidence interval. OR: odds ratio. HR: hazard ratio. Hs-CRP: high sensitivity C-reactive protein. NIHSS: National Institute of Health Stroke Scale. CsA: cyclosporine A. MRI: magnetic resonance imaging. mRS: modified Rankin scale. rt-PA: recombinant tissue-type plasminogen activator.