An Estimate of Analytical Bias in Meta-Analysis: A Case Study of the Controversy of Thrombolysis in Stroke
CCCF ePoster library. Donaldson L. Nov 7, 2018; 233391; 5
Dr. Lachlan Donaldson
Dr. Lachlan Donaldson
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Background: Intravenous thrombolysis remains the most widespread intervention for acute ischaemic stroke. Yet there is ongoing controversy regarding its use. One possible explanation for this ongoing controversy is the role of bias. Discussion of bias in meta-analysis has mostly been limited to the influence of publication bias and assessment of the quality of included studies. The possible role of analytical bias— that is, bias in the synthesis and reporting of collected data— has received less attention.


Objective: To systematically assess the benefits and harms of intravenous thrombolysis for patients with presumed acute ischaemic stroke and to use this analysis to explore the potential influence of analytical bias on meta-analysis outcomes.


Methods: A literature review was first performed to identify concerns regarding literature supporting the use of intravenous thrombolysis in acute ischaemic stroke.  Next, we conducted a systematic review and meta-analysis of randomised clinical studies of intravenous thrombolysis compared with control in patients with presumed acute ischaemic stroke. This analysis was designed prospectively, according to best practice. The effectiveness of thrombolysis on functional outcome, symptomatic intracranial haemorrhage, early mortality and mortality at final follow-up was assessed using a fixed-effect meta-analysis. Finally, analyses were repeated with various limitations in order to explore the potential effect of analytical bias. Meta-analysis outcome was compared to the base case using the Ratio of Odds Ratios and Number Needed to Treat.


Results: 26 studies that randomised 10,431 participants were included. In the base case, the use of thrombolysis was associated with an increased odds of good functional outcome, Odds Ratio (OR) 1.14 (95% confidence interval (CI) 1.04-1.25, p=0.004), but also a significantly increased risk of symptomatic intracranial haemorrhage, OR 4.28 (95% CI 3.34-5.48, p<0.0005) and an increased risk of early mortality, OR 1.51 (95% CI 1.27-1.78, p<0.0005).


In the secondary analysis, the odds of improved outcome associated with treatment varied depending on the definition of ‘good outcome’ used, OR 1.45 (95% CI 1.23- 1.70) to 0.99 (95% CI 0.89-1.11). Restricting analysis to rt-PA trials alone increased the odds of good functional outcome (1.20 (95% CI 1.08- 1.33), while analysis of Desmoteplase in isolation did not suggest a statistically significant benefit (OR 1.09 (95% CI 0.75- 1.59)). The use of data collected ‘per-protocol’ increased the odds of death, OR 1.88 (95% CI 1.36- 2.59), but reduced the odds of intra-cerebral haemorrhage, OR 1.75 (95% CI 1.29- 2.37). There were major differences in the outcome of various sensitivity analyses that incorporated the risk of bias of included trials, OR of good functional outcome 1.20 (95% CI 1.03 - 1.39) to 0.95 (95% CI 0.43 - 2.08)).


Conclusions: The primary analysis demonstrated evidence of increased early mortality and symptomatic intracranial haemorrhage but also of improved functional outcomes for patients treated with thrombolysis. Meta-analysis results were shown to be sensitive to potential analytical bias, reflecting the need for prospective and transparent meta-analysis design.


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