Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial.
With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.
Shibuya
M
M
Department of Neurosurgery, Nagoya University, Japan.
Suzuki
Y
Y
Sugita
K
K
Saito
I
I
Sasaki
T
T
Takakura
K
K
Nagata
I
I
Kikuchi
H
H
Takemae
T
T
Hidaka
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000328:Adult; D000368:Aged; D002118:Calcium / Q000037:antagonists & inhibitors*; D002544:Cerebral Infarction / Q000517:prevention & control; D004311:Double-Blind Method; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D015994:Incidence; D002532:Intracranial Aneurysm / Q000150:complications*; D002546:Ischemic Attack, Transient / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000209:etiology; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D007546:Isoquinolines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil; D002118:Calcium