There is a longstanding dispute between stroke neurologists and some emergency physicians over over the risk/benefit calculus for intravenous thrombolytics in treating AIS. The controversy dates back to the time of the early thrombolysis trials in the mid 1990s and early 2000s (links to two of the trials are shown below):
Each side has different opinions about the drivers for the controversy (disclaimer- I’m neither a stroke neurologist nor an ER physician, but rather a family physician/concerned bystander):
Some emergency physicians:
- thrombolytic trials in AIS did not convincingly show efficacy;
- the distribution of baseline features of enrolled subjects suggests that the randomization process might have been suboptimal/defective;
- results of the trials were “fragile” and therefore unreliable;
- we should question widespread adoption of a practice with dubious efficacy and which poses serious potential risks [i.e., intracranial hemorrhage (ICH)];
- unless the AIS diagnosis is secure, the risk/benefit calculus for thrombolysis will be unfavourable- the patient will incur a small but real risk of ICH, without a reasonable expectation of benefit;
Stroke neurologists:
- the evidence base supporting the urgency of AIS diagnosis and treatment within the 0-3 and/or 0-4.5 hour window is robust; statistical re-analyses of the original trials corroborate this benefit;
- knowledge of how brain tissue damage progresses over time underpins the time-sensitive nature of stroke treatment. The ideal time window for thrombolysis was not initially known; this explains why not all trials were positive. To this end, trials studying the efficacy of late thrombolysis shouldn’t be lumped with trials studying the efficacy of early thrombolysis;
- the skepticism of (some) ER physicians, while ostensibly hingeing on statistical arguments, might instead stem primarily from suboptimal confidence in diagnosing AIS rapidly and accurately (plausibly a bigger problem for ER MDs working in areas where neurology and imaging support could be suboptimal):
- health systems should focus on addressing gaps in infrastructure/stroke team support for ER physicians;
- the standard of care is to offer thrombolysis to eligible patients presenting with AIS. Additional trials examining the efficacy of early thrombolysis will not be forthcoming.
The statistical methods used in these trials seem very complex (likely beyond deep understanding by non-statisticians). Some of the key concepts include:
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how best to analyze ordinal outcomes;
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how best to show treatment effects graphically;
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the importance of identifying, prespecifying, and adjusting for important prognostic factors;
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how to interpret baseline between-arm covariate prognostic factor imbalances. What can we infer from them (if anything) about the integrity of the randomization apparatus? What are the implications (if any) for the validity of treatment effect estimates?;
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the pitfalls of:
- change from baseline analyses;
- dichotomizing ordinal outcomes;
- “fragility” index:
- NNT;
- subgroup analysis/“responder” analysis;
- evidence synthesis involving lumping of dissimilar trials.
Some criticism of AIS trials seems like it might be rooted in statistical misunderstanding. But it’s also important to ask whether the trial results might have been less contentious if slightly different statistical approaches had been used:
As-yet-unconvinced ER physicians are unlikely to change their minds about the efficacy of AIS thrombolysis. Many might question this stance. Sometimes, going against the herd turns out to be the correct approach. But, surely, it’s implausible that stroke neurologists, many ER physicians, and statisticians across multiple continents would have reached consensus on the importance of timely thrombolysis for eligible patients without good reason (?) We can always speculate about potential biases among experts who have built their careers around certain treatment approaches. But arguments rooted in accusations of bias are unverifiable and therefore unscientific. Ultimately, unwarranted skepticism of efficacious treatments can be as harmful to patients as unwarranted enthusiasm for non-efficacious treatments.