Underrepresentation of certain patient populations in RCTs informing guidelines: Does it matter?

This week JAMA Internal Medicine published a research letter reporting data on the underrepresentation of women, elderly patients, and racial minorities in RCTs used to inform cardiovascular guidelines. The authors state that RCTs are considered to be the highest level of evidence that should be used to inform guideline development. I would argue systematic reviews would even be better but I understand that questions to be addressed in guidelines often need individual RCTs to answer them.  They then state that “RCTs can have limited external validity”. What do you think?

The authors evaluated all references and then focused on RCTs that were cited in the ACC/AHA guidelines on atrial fibrillation, heart failure, and acute coronary syndromes. They extracted data on age, gender, ethnicity, and continents from which subjects were recruited. What did they find?

Female representation was highest in RCTs in atrial fibrillation (33%) followed by ACS (29%) and heart failure (29%). The next question you should ask is how does this compare to the actual gender representations of people affected by these diseases? In US registries of atrial fibrillation women make up 55% of patients, 42% in ACS registries, and 47% in heart failure registries. Thus women are underrepresented by up to 22%  in these studies but does this affect guideline recommendations? Another way to think about this is would more data change recommendations for women? Hard to know for sure but I suspect not. If enrollment is properly conducted I would think that those enrolled would be a sample of all women with atrial fibrillation, ACS and heart failure. Even though the sampling fraction is smaller as long as they are representative of all women with those problems there should be no bias. The statistical inferences could be affected due to small sample sizes though but the overall qualitative findings (ie benefit or harm) should not be affected.

As expected the majority of patients enrolled in these studies were white. Black patients constituted 19% of heart failure RCT patients and 6% of both afib and ACS patients. In US registries of heart failure, afib and ACS black patients make up 6%, 21%, and 11% respectively. Again I don’t have a problem with this if sampling was done properly.

Elderly (defined as those >75 yrs of age) are very underrepresented constituting only 2% of patients in all the RCTs combined. In this case guideline developers will have to rely on observational data or use expert opinion to inform recommendations.

Finally, the authors point out that 94% of enrolled patients came from North America or Europe. Is this a problem? I don’t think so for the US as ACC/AHA guidelines are developed to guide treatment of American patients. Patients from other underrepresented continents will have less direct evidence informing recommendations on their care. Consequently, those recommendations will be based more on expert opinion.

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