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Thrombolytic Treatment for Ischaemic Stroke: Could the Crisis of Confidence Have Been Avoided by Better Analysis of Trial Data?

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Abstract

In many countries, thrombolysis with intravenous alteplase has become a central part of acute stroke care in recent years, requiring radical restructuring of services. However, a significant minority of emergency and stroke physicians have always had serious doubts about the safety and efficacy of thrombolytic treatment, and in 2015 these prompted a major review of the licensing status of alteplase by the UK regulatory authorities. Subsequent dramatic headlines and media stories have called into question the integrity of researchers and clinicians and undermined public faith in medical research. How did this situation arise and what should be done to prevent a repetition as we enter the era of intra-arterial treatment for stroke?

Early intravenous alteplase increases the chances both of good recovery and of severe haemorrhage, so the risk/benefit balance must be assessed for individual patients according to stroke severity. For older patients and those with bigger strokes, the ‘good recovery’ criterion is an inefficient way of assessing treatment effects since few achieve full independence and differences between levels of functional impairment are ignored. This waste of information can be reduced by applying different criteria for ‘good’ and ‘poor’ outcomes in different prognostic groups (as clinicians do intuitively), hence increasing the number of patients contributing useful data. Such ‘three-way prognosis-based outcome’ analysis of existing and future trials could greatly increase the amount of relevant evidence to guide clinical decisions for individual patients across the range of stroke severity.

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Author information

Authors and Affiliations

  1. Stroke Unit, Sunderland Royal Hospital, Kayll Rd, Sunderland, SR4 7TP, UK

    David Barer

  2. Departments of Internal Medicine and Cardiology, Oslo University Hospital, Oslo, Norway

    Eivind Berge

Authors
  1. David Barer
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  2. Eivind Berge
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Corresponding author

Correspondence to David Barer.

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Funding

The authors have not received any funding for the preparation of this manuscript. Neither author has received funding from or has any financial interests in the manufacturers of alteplase or other thrombolytic agents.

Conflict of interest

DB was a local investigator in IST-3. EB was a coordinating investigator for IST-3 in Norway.

Appendix: Box 1

Appendix: Box 1

1.1 Shortcomings of fixed threshold efficacy analysis used in IPD meta-analysis and MHRA review (mRS 0 or 1 vs. >1)

  • Clinically unrealistic:

    • Unlikely to detect important benefits in more severe strokes (e.g. possible change from severe to mild disability)

  • Statistically inefficient:

    • Few patients with major strokes will cross the threshold and contribute to analysis

    • Outcome variability could be reduced by adjusting for stroke severity

1.2 Shortcomings of using death and ICH as the only safety indicators

  • Using death alone ignores disabling but non-fatal ICH

  • A valid indicator of harm should include both death and greater than expected disability for a given level of stroke severity

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Barer, D., Berge, E. Thrombolytic Treatment for Ischaemic Stroke: Could the Crisis of Confidence Have Been Avoided by Better Analysis of Trial Data?. Drugs Aging 34, 79–88 (2017). https://doi.org/10.1007/s40266-016-0432-8

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  • DOI: https://doi.org/10.1007/s40266-016-0432-8

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