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Potential consequences for recruitment, power, and external validity of requirements for additional risk factors for
Sally C Howard1, Ale Algra, Charles P Warlow
1Department of Clinical Neurology, University of Oxford, United Kingdom.
Insights
Adding extra eligibility criteria in stroke prevention trials, like vascular risk factors, doesn't significantly boost statistical power. Excluding patients without these factors may harm generalizability and prolong recruitment, making it hard to justify.
Area of Science:
- Clinical Trials
- Cardiovascular Research
- Stroke Prevention
Background:
- Eligibility criteria in randomized controlled trials (RCTs) impact the generalizability of findings.
- Recent stroke prevention trials have incorporated additional vascular risk factors to increase outcome events and statistical power.
Purpose of the Study:
- To evaluate the effectiveness of using additional vascular risk factors as eligibility criteria in stroke prevention trials.
- To determine if stricter criteria enhance statistical power without compromising generalizability.
Main Methods:
- Analysis of data from 3 stroke prevention trials and 1 hospital-referred series.
- Patients with transient ischemic attack or minor ischemic stroke were stratified by two sets of additional risk factors.
- Calculated risks for stroke, myocardial infarction, or vascular death based on the number of risk factors.
Main Results:
- Observed risk increased with the number of risk factors (P<0.01).
- Risks in patients with one or more risk factors were not substantially greater than in all patients.
- Excluding patients without risk factors could not be statistically justified, despite significant differences in their proportion (21-73%) between criteria sets.
Conclusions:
- The selection of patients based on additional vascular risk factors can vary significantly between similar criteria sets.
- The potential for additional criteria to reduce generalizability and extend recruitment outweighs statistical power benefits.
- Excluding patients without risk factors is difficult to justify due to negative impacts on external validity.
Background And Purpose:
Eligibility criteria determine the external validity (generalizability) of the results of randomized controlled trials. To increase the number of outcome events, and hence statistical power, some recent stroke prevention trials have required additional vascular risk factors for eligibility.
Methods:
To assess the merits of additional eligibility criteria in stroke prevention trials, we analyzed data from 3 trials and 1 hospital-referred series of patients with a transient ischemic attack or minor ischemic stroke. Patients were stratified according to 2 sets of additional risk factors similar to those used in recent trials (MATCH, SPORTIF and PRoFESS); risk of stroke, myocardial infarction, or vascular death was calculated in relation to the number of risk factors.
Results:
Although the observed risk during follow-up did increase with the number of risk factors present (P<0.01 for both sets), the risks in patients with > or =1 risk factors were not substantially greater than those in all patients. Consequently, although the proportions of patients with no risk factors in the 4 cohorts differed substantially between the 2 sets of eligibility criteria (21% to 28% versus 56% to 73%), in neither case could their exclusion be justified on statistical grounds.
Conclusions:
The degree of patient selection introduced by use of additional vascular risk factors as eligibility criteria for trials can differ substantially between apparently similar sets of risk factors. Given that the potential for additional eligibility criteria to undermine generalizability and prolong recruitment outweighs any benefits in terms of statistical power, the exclusion of patients with no risk factors is difficult to justify.
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