10-Year evolution in worldwide usage of anticoagulant drugs

The administration of anticoagulant drugs is a mainstay in prevention and management of a kaleidoscope of thrombotic disorders.[1] In relatively recent periods, and more specifically at the beginning of this last century, the armamentarium of such drugs—which had basically comprised vitamin K antagonists (VKAs) and heparin (either unfractionated or low molecular weight) for long—has been considerably magnified with development, clinical validation, and further commercialization of the so-called direct oral anticoagulants (DOACs).[2] These were considered “new” or “novel” agents at the time of release, and thus given the earlier abbreviation of NOACs, which has persisted in some publications, as potentially now defined as “non-vitamin K antagonist oral anticoagulants.” The DOACs are mostly represented by the thrombin inhibitor dabigatran and the activated factor X (FXa) inhibitors apixaban, edoxaban, and rivaroxaban, and present several advantages over VKAs and heparin, so that their usage has constantly increased over time, all around the world, as shown by an infodemiological analysis that we performed in 2017.[3] Similar findings have been reported in geographically specific localities such as Australia.[4] Since the clinical indications and dosage of these drugs have both constantly evolved over time,[5] we aim to provide here an update with infodemiological data reflecting the global volume of Web searches for these medications during the past 10 years, which is now known to reliably mirror their real-world usage.[6]

We accessed Google Trends (Google Inc. Mountain View, CA) using the medical terms “dabigatran,” “apixaban,” “edoxaban,” “rivaroxaban,” and “heparin,” setting first the geographical location to “worldwide” and then to the United States, the United Kingdom, or Australia, and limiting the search output to the past 10 years (i.e., between July 2012 and July 2022). The monthly Google Trends score for all such terms, thus mirroring their Web worldwide popularity and probable usage over time, was downloaded into a Microsoft Excel spreadsheet (Microsoft, Redmond, WA), where it was digitally and statistically analyzed with Mann–Whitney test (Analyze-it Software Ltd, Leeds, UK).

The main results of this infodemiological analysis are shown in [Fig. 1]. On a worldwide scale, a consistent increase can be seen for the monthly Google Trends score of heparin, rivaroxaban, and apixaban, displaying rather confrontable values at the end of the search period. A modest increase could also be seen for the monthly Google Trends score of edoxaban, while that of dabigatran has mostly remained stable throughout the observational period. Notably, the most recent median value of the monthly Google Trends score (i.e., from January to July 2022) was the highest for heparin (median, 78; interquartile range (IQR), 76–84), which was nonstatistically different from that of apixaban (median, 75; IQR, 72–84; p = 0.408) and rivaroxaban (median, 67; IQR, 66–83; p = 0.159), but was still considerably higher than that of edoxaban (median, 9; IQR, 9–10; p 
As concerns the other three countries that we have explored in our infodemiological analysis, the monthly Google Trends score of apixaban displayed the most accentuated increase over time, becoming by far the most frequently searched drug in 2022. The monthly Google Trends scores of rivaroxaban and heparin remained rather stable over time, while those of edoxaban and dabigatran reflected the worldwide figure, displaying considerably low values throughout the search period. The UK data are similar to those of the United States, with the monthly Google Trends score of apixaban displaying again the sharpest increase over time and being by far the most searched anticoagulant drug at the end of the period, followed by rivaroxaban and heparin. A gradual increase could also be noted for the monthly Google Trends score of edoxaban, while that of dabigatran displayed a progressive decrease over time. Australian data, finally, are aligned with the worldwide trend, evidencing a gradual increase in the monthly Google Trend score of apixaban (which is, again, the most searched anticoagulant drug in the country), followed by rivaroxaban and heparin. The monthly Google Trend score of dabigatran has remained relatively stable over time, while that of edoxaban was always very low throughout the search period.

The results of this infodemiological analysis suggest that apixaban seems to be the most searched anticoagulant drug all around the world, as well as in some specific and representative countries like the United States, the United Kingdom, and Australia, thus likely mirroring its high worldwide usage. For Australia, this also mirrors usage data based on prescription data.[4] The volume of worldwide Google searches for heparin has also increased over time, exhibiting a considerable peak after the 2020, in concomitance with the emergence of the coronavirus disease 2019 (COVID-19) pandemic.[7] This is quite predictable, since COVID-19 is associated with a considerable burden of thrombotic complications, both venous[8] and arterial,[9] and heparin is still considered the drug of choice for managing these patients.[10] As concerns the other drugs, rivaroxaban seems to be still widely used worldwide, as reflected by the conspicuous and constantly increasing number of Google worldwide searches. A modest increase can also be observed for edoxaban, more evident in the United Kingdom, and likely reflecting the lower number of medicinal agencies which have approved its usage all around the world. Dabigatran, finally, has remained by far the lowest searched drugs in the past 10 years, displaying a trend that seems to decrease further, and thus possibly highlighting the (toward commercial) expiry of direct antithrombin inhibitors. There is no definitive explanation for this evidence, though there is general perception that anti-FXa inhibitors may have better safety profile (especially lower risk of bleeding, as recently evidenced),[11] [12] while they also have broader range of clinical applications compared with direct thrombin inhibitors.
In conclusion, we believe that the results of this infodemiological analysis may provide valuable clues reflecting the evolution over (recent) time of the worldwide usage of anticoagulant drugs, since this information may influence health care organization in a broad perspective, in terms of drug monitoring (and thereby clinical laboratory organization)[13] and prevention of side effects (and hence development, commercialization, and procurement of antidotes).[14]