Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study. Phase II trial of tirilazad in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study. Prevention and treatment of supraventricular tachycardia shortly after coronary artery bypass grafting: a randomized open trial. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Dipyridamole and postoperative ischemic deficits in aneurysmal subarachnoid hemorrhage. Supraventricular tachyarrhythmias after coronary bypass surgery--a double blind randomized trial of prophylactic low dose propranolol. Significance of Supraventricular Tachyarrhythmias After Coronary Artery Bypass Graft Surgery and Their Prevention by Low-Dose Sotalol: A Prospective Double-Blind Randomized Placebo-Controlled Study.
To assess the safety and feasibility of a clinical trial on the effectiveness of acetylsalicylic acid (ASA) in subarachnoid hemorrhage (SAH).
                Several studies have indicated that increased platelet activity might be involved in the pathogenesis of delayed cerebral ischemia (DCI) after SAH.
                Fifty patients who had early surgery (< or =4 days) for a ruptured aneurysm were enrolled in this randomized, double-blind, placebo-controlled trial. Trial medication, consisting of suppositories with 100 mg ASA versus placebo, was started immediately after surgical clipping of the aneurysm and continued for 21 days. End points were functional outcome and quality of life at 4 months, clinical deterioration after operation, development of DCI, hypodense lesion on postoperative CT, and hemorrhagic complications.
                One-third of all patients with aneurysmal SAH were eligible for the trial. Fifteen of 26 patients receiving placebo deteriorated clinically versus 10 of 24 patients receiving ASA; 4 patients in each group deteriorated from DCI. Postoperative hypodensities on CT were observed in 27 patients, distributed equally in both groups. Functional outcome and quality-of-life scores were slightly in favor of patients who had received ASA, but not to a significant degree (p = 0.22). Two patients in the ASA group had an asymptomatic hemorrhagic complication, and one patient in the placebo group had a fatal and another a symptomatic hemorrhagic complication.
                This pilot study shows that a clinical trial of acetylsalicylic acid (ASA) in subarachnoid hemorrhage (SAH) is feasible and probably safe. The effectiveness of ASA on functional outcome and delayed cerebral ischemia has to be studied in a larger trial. A previous systematic review of randomized trials suggested a positive effect of antiplatelet therapy in patients with aneurysmal subarachnoid hemorrhage (SAH). We performed a randomized controlled trial to assess whether acetylsalicylic acid (ASA) reduces the risk of delayed ischemic neurological deficit (DIND) in patients with SAH.
                Criteria for inclusion were aneurysm treatment within 4 days after SAH. Trial medication (14 daily suppositories with 100 mg ASA or placebo) was started within 12 hours after aneurysm treatment. Analysis for the primary outcome event DIND was made according to the "on-treatment" principle and for the secondary outcome measures "poor outcome" and "nonexcellent outcome" according to the "intention-to-treat" principle.
                Inclusion was stopped after the second interim analysis, when 161 of the planned 200 patients were included, because by then the chances of a positive effect were negligible. At the final analysis, ASA did not reduce the risk of DIND (hazard ratio, 1.83; 95% CI, 0.85 to 3.9). The relative risk reduction for poor outcome was 21% (relative risk, 0.79; 95% CI, 0.38 to 1.6).
                ASA given after aneurysm treatment does not appreciably reduce the occurrence of DIND. Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A trend toward improvement in overall 3-month patient outcome was seen in the 2 mg/kg per day tirilazad-treated group compared to the outcomes in the vehicle-treated groups. We conclude that tirilazad mesylate is safe in SAH patients at doses up to 6 mg/kg per day for up to 10 days and is a promising drug for the treatment of patients with aneurysmal SAH. A total of 216 patients with a ruptured aneurysm of the anterior part of the circle of Willis were enrolled into this prospective randomized study of timing of the operation after aneurysmal subarachnoid hemorrhage (SAH). Only patients in clinical Grades I to III (according to the classification of Hunt and Hess) who were admitted and randomly assigned to a treatment group within 72 hours after the SAH were included in the trial. The patients were randomly assigned to one of three operation groups: acute surgery (AS: 0 to 3 days after the SAH; day of SAH = Day 0), intermediate surgery (IS: 4 to 7 days after the SAH), or late surgery (LS: 8 days to an indefinite time after the SAH). Three patients (4.3%) in the IS group and six patients (8.6%) in the LS group died before surgery was undertaken. At 3 months post-SAH, 65 patients (91.5%) from the AS group were classified as independent compared to 55 (78.6%) from the IS group and 56 (80.0%) from the LS group. The management mortality rate in the AS group was 5.6% compared to 12.9% in the LS group. Of the 216 patients enrolled in the timing study, 159 were randomly assigned to an independent double-blind placebo-controlled trial of nimodipine in Grade I to III patients. A total of 79 patients received nimodipine and 80 placebo. When the nimodipine group and the no-nimodipine group (the 80 placebo-treated patients plus the 52 patients who were not entered into the nimodipine trial) were analyzed separately, a significant difference was seen in the outcome of the no-nimodipine group (dependent AS vs. dependent IS, p = 0.01). Nimodipine treatment was associated with a significant reduction of delayed ischemic deterioration (all operation group combined, nimodipine vs. no nimodipine p = 0.01; LS with nimodipine vs. LS with no nimodipine, p = 0.03). Supraventricular arrhythmias continue to complicate the postoperative course of patients following coronary artery bypass grafting. In a randomized, open, controlled trial we assessed the value of two different beta-blocking agents in the prevention and treatment of these arrhythmias. Of 151 consecutive patients undergoing coronary artery surgery, 39 were treated with metoprolol and 41 were treated with sotalol (a beta blocker with class III antiarrhythmic properties). Fifty patients served as a control group and received no prophylactic therapy. Twenty-one patients were eliminated from the study for various reasons, making a final total of 130 in the study group. In the metoprolol group 15.3% of patients developed supraventricular tachycardia SVT after coronary artery surgery, which was significantly less (p less than 0.05) than the incidence observed in the control group. However, in the group of patients receiving sotalol, 2.4% developed SVT (p less than 0.01 compared with the control group). Of 18 patients in the control group who developed SVT after randomization, 10 received sotalol and 4 metoprolol to terminate the arrhythmia. The mean time of termination of SVT after drug administration was 2.4 +/- 1.8 hours for treatment with sotalol and 13.6 +/- 9.8 hours for treatment with metoprolol. We conclude that sotalol significantly reduces the incidence of supraventricular tachycardia in the early period after coronary artery bypass surgery. Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH.
                Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of > or =1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean V(MCA) >160 m/sec).
                There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100beta were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103+/-41 versus 149+/-47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20).
                The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit. Recent evidence has suggested that the delayed cerebral ischemic deficits that often follow surgery for aneurysmal subarachnoid hemorrhage (SAH) may be due to a proliferative vasculopathy. This vascular pathology may result from an interaction between the platelets and the vessel wall. A single-blind controlled trial of dipyridamole administration in 677 patients presenting with SAH (of whom 348 came to surgery) was undertaken to test the hypothesis that the modification of platelet behavior might reduce the incidence of ischemic deficits. Blind independent assessment of the outcome in the surgical group based on the Glasgow Outcome Scale and the specific neurological deficits revealed no significant differences between the control and treatment groups. In the present study 75 patients were double blind randomized either to receive 10 mg propranolol orally 4 times a day (35 patients) or a placebo (40 patients). Episodes of clinically important supraventricular tachyarrhythmias were recorded in the first 4 postoperative days. They appeared in 5 of 35 patients receiving propranolol and in 5 of 40 patients receiving placebo (no statistically significant difference). In conclusion this study indicates the need for further evaluation to clarify if low-dose propranolol or any other drug is effective in reducing the frequency of SVT in the early postoperative period after coronary artery bypass surgery. BACKGROUND: The single most frequent complication after coronary artery bypass graft surgery is the occurrence of supraventricular tachyarrhythmias leading to a prolonged hospital stay. Although several drugs have been used to treat these arrhythmias, effective prevention was only possible with beta-blocking drugs in selected patients. It was, therefore, the aim of the present study to evaluate the significance of supraventricular tachyarrhythmias in presence of today's cardioprotective management in a broad spectrum of patients and to assess the possible preventive effect and safety of low-dose sotalol after coronary artery bypass graft surgery. METHODS AND RESULTS: In a prospective randomized double-blind placebo-controlled trial, 220 consecutive patients referred for elective coronary artery bypass graft surgery were randomized to 80 mg sotalol twice daily (n = 110) or matching placebo (n = 110) for 3 months with the first dose given 2 hours before surgery. There were no significant differences in baseline characteristics between the two groups. Low-dose sotalol reduced the rate of supraventricular arrhythmias from 43% (placebo) to 25% (sotalol, P <.01), which was atrial fibrillation in 83%, flutter in 7%, and other supraventricular arrhythmias in 10%. Only 7% of all arrhythmias were observed after day 9. Hospital stay was 11 +/- 4 days in patients with supraventricular arrhythmias versus 9 +/- 2 days (P <.001) in patients without. On the fourth postoperative day, heart rate was lower in the sotalol group (75 +/- 12 versus 86 +/- 14 beats per min; P <.0001), but QTc was not significantly prolonged (sotalol, 0.44 +/- 0.03; placebo, 0.43 +/- 0.03; P, ns). Study medication had to be discontinued due to side effects in 6.4% of sotalol and 3.6% of placebo patients (P, ns), but relevant side effects occurred only in two sotalol patients late after surgery. CONCLUSIONS: These data show that without antiarrhythmic therapy the incidence of supraventricular arrhythmias after coronary artery bypass graft surgery is high (43%) and that supraventricular arrhythmias were associated with a prolonged hospital stay (+/-2 days). Prophylactic treatment with low-dose sotalol reduced the incidence of supraventricular arrhythmias significantly (by 40%), thereby reducing overall hospital stay in treated patients. Because more than 90% of all supraventricular arrhythmic episodes occurred within 10 days after surgery and considering the small proarrhythmic effect of sotalol late after surgery, prophylactic treatment with sotalol may be recommended for the first 10 postoperative days to safely reduce supraventricular tachyarrhythmias.
We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial. More RCTs are needed.