Hemostatic Drug Therapies for Acute, Nontraumatic Intracerebral Hemorrhage

Objective

We sought to determine the clinical effectiveness and safety of hemostatic drug therapies for acute nontraumatic ICH in randomized controlled trials (RCTs).

Search Strategy

In August 2005 we searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE from 1966 and EMBASE from 1980. We also scanned bibliographies of relevant articles, searched international registers of clinical trials and research, and contacted authors and pharmaceutical companies.

Selection Criteria

We sought randomized controlled trials of any hemostatic drug therapy for acute nontraumatic ICH, compared against placebo or open control, with relevant clinical outcome measures.

Data Collection and Analysis

Two review authors (R.A.-S., H.Y.) independently applied the inclusion criteria, reviewed the relevant studies, and extracted data from them.

Main Results

We found 4 phase II RCTs, involving adults aged 18 years or over, within 4 hours of nontraumatic ICH. One hundred and sixteen study participants received placebo and 373 received hemostatic drugs (2 received ε-aminocaproic acid and 371 received recombinant activated factor VII [rFVIIa]).

Hemostatic drugs reduced the relative risk of death within 90 days of nontraumatic ICH (risk reduction [RR] 0.67; 95% CI, 0.46 to 0.97, random effects; Figure). Specifically, rFVIIa appeared to reduce the risk of death or dependence on the modified Rankin Scale (grades 4 to 6) within 90 days of nontraumatic ICH (RR 0.79; 95% CI, 0.67 to 0.93) but not when assessed by the extended Glasgow Outcome Scale (RR 0.90; 95% CI, 0.81 to 1.01). A statistically significant excess of arterial thromboembolism at 160-μg/kg rFVIIa has been found in the trials (odds ratio 7.17, P=0.0004 versus placebo¹).

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Effect of hemostatic drugs compared with placebo or open control on death at 90 days of follow-up in patients with acute, nontraumatic intracerebral hemorrhage. ATICH was a trial of ε-aminocaproic acid

Implications for Clinical Practice

The evidence for the use of hemostatic drugs in the treatment of acute ICH is insufficient to provide clear guidelines for practice but should influence priorities for research.

Implications for Research

The clinical benefits of hemostatic drugs for acute nontraumatic ICH that have been observed among the secondary outcomes in phase II RCTs have led to a large phase III RCT of rFVIIa (FAST trial, NCT00127283). The FAST trial must (1) confirm or refute the apparent effects of rFVIIa on death or dependence and (2) provide more reliable evidence on whether any benefit from reduced hematoma growth is offset by an increase in arterial and venous thromboembolic events.

Evidence of the effects of less costly hemostatic drugs (for example, aprotinin, tranexamic acid, and ε-aminocaproic acid) in other clinical settings suggests that these drugs are also worth testing in large RCTs in people with acute nontraumatic ICH.

Note: The full text of this review is available in the Cochrane Library (for subscribers http://www.mrw.interscience.wiley. com/cochrane/clsysrev/articles/CD005951/frame.html). The full article should be cited as: You H, Al-Shahi R. Hemostatic drug therapies for acute primary intracerebral hemorrhage. Cochrane Database of Systematic Reviews. 2006, Issue 3. Art. No.: CD005951. DOI: 10.1002/14651858.CD005951.pub2.