A review of 21 trials of oral antithrombotic medications found that the published rate of patients lost to follow-up was significantly lower than the FDA’s follow-up calculations.
Lead researcher Thomas A. Marciniak, MD, a former medical team leader in the FDA’s cardiorenal division, and colleagues published their findings online in JAMA Internal Medicine on Jan. 11.
“The published rates consistently seem to be inadequate representations of the completeness and quality of follow-up,” they wrote. “The extent to which the FDA-calculated rates exceed the end point rate differences implies that the end point differences may be due to differential follow-up rather than drug effect.”
The researchers followed the same method Marciniak used when worked at the FDA. They counted patients as having incomplete follow-up if the last contact date at which end points were ascertained was before the earliest last follow-up date as defined by the study’s documents. They also obtained drug discontinuation rates from the FDA’s review and calculated primary end point differences and incomplete follow-up rates.
The 21 trials in this analysis randomized a total of 270,089 patients to receive treatment for a median of 20 months. The last enrollment dates for the studies were from 1995 to 2011.
The oral antithrombotics studied were apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Savaysa), rivaroxaban (Xarelto), ximelagatran (Exanta), clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta) and vorapaxar (Zontivity).
The mean published rate of loss to follow-up was 0.4 percent, while the mean FDA-calculated incomplete follow-up rate was 12 percent. The researchers said there was no correlation between the published and FDA-calculated rates.
The mean drug discontinuation rate was 24.9 percent and was not correlated with publication or FDA-calculated follow-up rates.
In addition, the FDA-calculated rates of loss to follow-up were larger than the end point rate difference, while the published rates of loss to follow-up are typically less than the end point difference.
Although Marciniak used to work at the FDA, the authors noted that “the opinions expressed are our own and should not be construed as official FDA policy.”
They recommended that the FDA consider incomplete follow-up rates as important estimates of the reliability of trials.
“Prior studies have reported similar controversy regarding published rates of loss to follow-up,” they wrote. “Our unique contribution is the comparison with the FDA independent assessment of follow-up completeness. It is clear that capturing and reporting of follow-up must be improved for better confidence in the validity of trial results. We suggest the FDA-calculated follow-up assessment methodology as a start.”