To compare the risk of intracranial haemorrhage in patients treated with bolus versus infusion thrombolytic therapy.

MEDLINE and the Cochrane Controlled Trials Register were searched from 1980 to 1999 using the following terms: 'Thrombolytic therapy', 'acute myocardial infarction', 'alteplase', 'duteplase', 'reteplase', 'lanoteplase', 'tenecteplase', 'saruplase', 'streptokinase', 'urokinase' and 'anistreplase'. In addition, the reference lists from review articles and published abstracts from Scientific Sessions of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched manually from January 1994 to November 1999.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) of open-label or double-blind design, with a sample size of greater than 1000, were included.

Specific interventions included in the review

Studies had to compare thrombolytic therapy administered as a single or double bolus over no more than 5 minutes, with infusion administration of the same or similar agents over at least 30 minutes.

The bolus agents were: anistreplase (30 U), reteplase (10 MU), alteplase (40 to 50 mg), saruplase (80 mg), tenecteplase (30 to 50 mg) and lanoteplase (120 kU/kg).

The infusion comparators were: streptokinase (1.5 MU), duteplase (0.60 U/kg), alteplase (up to 100 mg) and saruplase (80 mg).

Dose-ranging studies were excluded.

Participants included in the review

Studies of patients with acute coronary syndrome with ST elevation were eligible for inclusion. The mean age of participants in each trial was between 61 and 63 years, and more than 70% were men. The proportion of participants age at least 75 years ranged from 12 to 14%. The prevalence of diabetes was between 11 and 16%, and the prevalence of hypertension was between 33 and 39%. The mean baseline systolic blood-pressure of participants was between 135 and 140 mm Hg.

Outcomes assessed in the review

No inclusion criteria relating to outcomes were specified.

The outcomes assessed in this review were intracranial haemorrhage, non- haemorrhagic stroke (all strokes other than definite or probable intracranial haemorrhage), all-cause mortality and reinfarction.

How were decisions on the relevance of primary studies made?

Two independent reviewers selected the studies and any disagreements were resolved by discussion.

The quality of the trials was not formally assesssed. Data on whether the trials were of open-label or double-blind design were extracted.

The authors do not state how the data were extracted for the review, or how many of the reviewers performed the data extraction. Data were extracted on: computed tomography or magnetic resonance imaging; confirmed or probable (strongly suggested by the clinical signs or symptoms) primary intracranial haemorrhage; non-haemorrhagic stroke, i.e. all strokes other than definite or probable intracranial haemorrhage; all-cause mortality at 30 days; and reinfarction. When the reported or published data were incomplete, the original authors were contacted for additional details. The following details were tabulated for each trial: year of publication, number of patients, median age, proportion of men, design of study, bolus agent, number of boluses, and comparator agent.

How were the studies combined?

Data from the individual trials were combined using a fixed-effect model, according to the modified Mantel-Haenszel approach described by Yusuf et al. (see Other Publications of Related Interest).

How were differences between studies investigated?

Formal statistical tests for heterogeneity were performed.

In total, 7 studies involving 10,3972 patients were included.

Intracranial haemorrhage and non-haemorrhagic stroke (7 trials).

The risk of intracranial haemorrhage was significantly increased when using bolus thrombolytic agents, compared with administration by infusion. The odds ratio (OR) was 1.25 (95% confidence interval, CI: 1.08, 1.45). The study results were homogeneous (p=0.27).

The incidence of non-haemorrhagic strokes did not differ between bolus and infusion strategies (OR 0.94, 95% CI: 0.81, 1.09). The study results were homogeneous (p=0.81), but there was a non significant trend towards an increase in total stroke (OR 1.08, 95% CI: 0.97, 1.20).

Mortality and reinfarction.

The 30-day mortality rate was 8.4% (4,034 out of 50,195) in the patients receiving bolus treatment, compared with 8.3% (4,711 out of 53,747) in the infusion group. The OR was 1.01 (95% CI: 0.96, 1.06). The study results were homogeneous (p=0.99).

Reinfarction occurred in 4.0% (2,029 out of 50,034) of the patients receiving bolus treatment, compared with 3.9% (1,990 out of 53,414) of the patients in the infusion group. The OR was 1.04 (95% CI: 0.97, 1.11). The studies were homogeneous (p=0.27).

The increased risk of bolus thrombolytic treatment seemed to be associated primarily with the method of administration, rather than the properties of the agents. Although the increased risk of intracranial haemorrhage is small, physicians should balance this risk against the putative benefits of easier administration with no difference in mortality and reinfarction.

This review was presented clearly and the study question was clearly defined. There was a lack of comprehensive information on the search strategy used, and additional databases, e.g. EMBASE, could have been searched. The authors did not state whether they had contacted pharmaceutical companies or experts in the field for additional material, and they did not report any language restrictions for published articles.

No formal quality assessment was conducted. However, only large RCTs (greater than 1,000 participants) were included, and the authors reported on whether these trials were of open-label or double-blind design. Studies were synthesised appropriately. Details of the review process were reported, and appropriate study details were presented in tabular format. The authors' conclusions were supported by the results.

Practice: The authors state that there seems little justification for the introduction of bolus thrombolytic therapy into routine practice in hospitals, unless future studies show that the convenience of bolus administration materially increases the appropriate use of thrombolytic treatment overall without risk. Since none of the included trials compared the same two drugs, there is insufficient evidence to prevent the introduction of a potentially useful mode of delivery.

Research: The authors state that newer strategies, such as combined lower-dose thrombolytic therapy and glycoprotein-IIb/IIIa-receptor inhibitors, might have similar efficacy and perhaps even greater safety. These should be tested in adequately powered randomised trials.

Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71.

These additional published commentaries may also be of interest. Intracranial haemorrhage with bolus thrombolytic agents [letters]. Lancet 2000;356:1848-50.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.