Prophylactic nimodipine treatment for cochlear and facial nerve preservation after vestibular schwannoma surgery: a randomized multicenter Phase III trial

Abstract

obJective A pilot study of prophylactic nimodipine and hydroxyethyl starch treatment showed a beneficial effect on facial and cochlear nerve preservation following vestibular schwannoma (VS) surgery. A prospective Phase III trial was undertaken to confirm these results. methods An open-label, 2-arm, randomized parallel group and multicenter Phase III trial with blinded expert review was performed and included 112 patients who underwent VS surgery between January 2010 and February 2013 at 7 departments of neurosurgery to investigate the efficacy and safety of the prophylaxis. The surgery was performed after the patients were randomly assigned to one of 2 groups using online randomization. The treatment group (n = 56) received parenteral nimodipine (1-2 mg/hr) and hydroxyethyl starch (hematocrit 30%-35%) from the day before surgery until the 7th postoperative day. The control group (n = 56) was not treated prophylactically. results Intent-to-treat analysis showed no statistically significant effects of the treatment on either preservation of facial nerve function (35 [ ]) (p = 0.530) 12 months after surgery. Since tumor sizes were significantly larger in the treatment group than in the control group, logistic regression analysis was required. The risk for deterioration of facial nerve function was adjusted nearly the same in both groups ], p = 0.91). In contrast, the risk for postoperative hearing loss was adjusted 2 times lower in the treatment group compared with the control group (OR 0.49 [95% CI 0.18-1.30], p = 0.15). Apart from dosedependent hypotension (p < 0.001), no clinically relevant adverse reactions were observed. coNclusioNs There were no statistically significant effects of the treatment. Despite the width of the confidence intervals, the odds ratios may suggest but do not prove a clinically relevant effect of the safe study medication on the preservation of cochlear nerve function after VS surgery. Further study is needed before prophylactic nimodipine can be recommended in VS surgery.Clinical trial registration no.: 2009-012088-32 (www.clinicaltrialsregister.eu)

Nimodipine but Not Nifedipine Promotes Expression of Fatty Acid 2-Hydroxylase in a Surgical Stress Model Based on Neuro2a Cells

“…In cell culture as well as in clinical approaches pre-treatment with nimodipine seems to be required for better hearing preservation and/or nerve function after vestibular schwannoma surgery and better survival of cells, respectively [14,15,20]. While optimal pre-treatment period for cell culture is 24 h [20], best pre-treatment period for patients still needs to be defined.…”

“…Nimodipine is recommended for the management of aneurysmal subarachnoid hemorrhage (aSAH) and has a proven effect in reducing poor outcome and delayed ischemic neurological deficits (DIND) following aSAH [5,6]. In skull base, laryngeal and maxillofacial surgery in animal experiments [7,8,9,10], and clinical series it shows a beneficial effect [11,12,13,14,15,16]. These results were linked to neuroprotection described by Nuglisch et al [17].…”

Editorial. Nimodipine treatment

“…The previously performed Phase III trial in 112 patients, a study in which facial nerve function 12 months after surgery was the primary outcome, showed no significant effects. 4 However, the risk for postoperative hearing loss was 2 times lower in the treatment group compared to the control group (OR 0.49, 95% CI 0.18-1.30; p = 0.15), particularly in medium and large tumors (Koos III and IV). Therefore a continuation Phase III RCT with hearing preservation as the primary outcome in patients suffering from medium to large VSs and who have preoperative useful hearing ability is mandatory.…”

Prophylactic nimodipine treatment and improvement in hearing outcome after vestibular schwannoma surgery: a combined analysis of a randomized, multicenter, Phase III trial and its pilot study

“…19 A Phase III trial with facial nerve function assessed 12 months after surgery as the primary outcome showed no significant results. 22 However, the risk for postoperative hearing loss was 2 times lower in the treatment group compared with the control group. Several factors are known to have an impact on the outcome of both the facial and cochlear nerves following VS surgery.…”

“…20,28 The concept of a prophylactic administration of nimodipine and HES arose from these observations. 19,22 Considering the positive effect of prophylactic nimodipine and HES on hearing preservation in the presented combined analysis gives rise to the following questions. Because pharmacokinetic studies of prophylactically administered nimodipine in skull base surgery showed that parenteral nimodipine produces higher drug levels and has a higher neuroprotecive efficacy as compared with enteral administration, parenteral nimodipine seems to be superior.…”