Elsevier

The Lancet Neurology

Volume 5, Issue 12, December 2006, Pages 1029-1032
The Lancet Neurology

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Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review

https://doi.org/10.1016/S1474-4422(06)70582-8Get rights and content

Summary

Background

Despite several randomised controlled trials, there is still much debate whether nimodipine improves outcome in patients with traumatic subarachnoid haemorrhage. A 2003 Cochrane review reported improved outcome with nimodipine in these patients; however, because the results of Head Injury Trial (HIT) 4 were only partly presented there is still discussion whether patients with traumatic subarachnoid haemorrhage should be treated with this drug. Here, we present data from all head-injury trials, including previously unpublished results from HIT 4.

Methods

We systematically searched PubMed and EMBASE databases using the following combinations of variables: “nimodipine” or “calcium antagonist” with “traumatic subarachnoid haemorrhage”, “head injury”, “head trauma”, “brain injury”, or “brain trauma”. Bayer AG and all principal investigators or corresponding authors of the identified studies were contacted for additional information.

Findings

Five manuscripts were identified, describing the results of four trials. We obtained additional data from HIT 1, 2, and 4. In total, 1074 patients with traumatic subarachnoid haemorrhage were included. The occurrence of poor outcome was similar in patients treated with nimodipine (39%) and those treated with placebo (40%); odds ratio was 0·88 (95% CI 0·51–1·54). Mortality rates did not differ between nimodipine (26%) and placebo (27%) treated patients (odds ratio 0·95; 95% CI 0·71–1·26).

Interpretation

Our results do not lend support to the finding of a beneficial effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage as reported in an earlier Cochrane review.

Introduction

In patients with aneurysmal subarachnoid haemorrhage, nimodipine has been shown to be effective in the prevention of ischaemic complications after haemorrhage resulting in improved outcome.1 Since nimodipine is believed to have neuroprotective properties, the drug was suggested to be of potential benefit in patients with traumatic head injury.

The first report on nimodipine treatment in patients with severe head injury dates from 1984.2 The first randomised controlled trials investigating the effect of nimodipine in head injury the Head Injury Trials (HIT) 1 and 2 were published in the early 1990s.3, 4 In the overall analysis of these studies, no reduction in poor outcome was shown. However, in a subgroup analysis of HIT 2, a possible beneficial effect was noted in patients with traumatic subarachnoid haemorrhage. Because of these findings, HIT 3 was initiated in which only head-injury patients with traumatic subarachnoid haemorrhage were included.5 The HIT 3 study showed a small but significant beneficial effect in nimodipine-treated patients. To confirm this favourable effect in a much larger group of patients, HIT 4 was started. Unexpectedly, HIT 4 showed a significant increase in poor outcome in nimodipine-treated patients. Possibly because of this disappointing result, the results of HIT 4 have never been published in detail, but some of the results were presented at a conference.

In 2003, a Cochrane review on the effects of calcium antagonists on outcome in patients with head injury was published, which concluded that there is no beneficial effect of nimodipine on outcome in head-injury patients.6 However, in the subgroup of patients with traumatic subarachnoid haemorrhage nimodipine was shown to improve outcome.

Because the results of HIT 4 were only partly presented, there is still much debate as to whether patients with traumatic subarachnoid haemorrhage should be treated with nimodipine. Here we present for the first time the data of all head-injury trials, including previously unpublished results from the HIT 4 trial.

Section snippets

Search strategy and selection criteria of studies

We systematically searched the electronic PubMed and EMBASE databases up to 2006 (week 10) for the following combinations of variables: “nimodipine” or “calcium antagonist” with “traumatic subarachnoid haemorrhage”, “head injury”, “head trauma”, “brain injury”, or “brain trauma”. Randomised controlled studies from the English, German, and French published work were included. Animal studies were excluded. Bayer AG and all principal investigators or corresponding authors of the identified studies

Results

By searching the electronic databases of PubMed and EMBASE five manuscripts were identified, describing the results of four trials.3, 4, 5, 9, 10 The principal investigators of HIT 1 and 2 were contacted for additional data on outcome and access was granted to both original datasets. For HIT 3, only published data were available. Bayer AG was contacted for the data of HIT 4, but they advised us to contact the principal investigator of HIT 4. The principal investigator of HIT 4 granted us

Discussion

The occurrence of poor outcome and mortality rates did not differ between patients treated with nimodipine and those treated with placebo. Our results contrast with those of the Cochrane review published in 2003, which showed that nimodipine significantly reduced poor outcome and mortality in patients with traumatic subarachnoid haemorrhage. The present analysis differs in three aspects from the Cochrane analysis. First, we restudied the original data of HIT 1 so that mortality rates of HIT 1

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