Scripties UMCG - Rijksuniversiteit Groningen
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In patients with atrial fibrillation treated with apixaban, do extremes in drug levels play ameaningful role in the high rates of stroke and bleeding observed in clinical practice?

(2018) Vries, T.A.C. de (Tim)

Apixaban is a direct acting oral anticoagulant (DOAC) approved for stroke prevention in patients with atrial fibrillation (SPAF). This DOAC was tested with success in two phase III trials (AVERROES and ARISTOTLE), in which it was dosed according to an explicit dosing strategy: 5 mg twice daily (BID) or 2.5 mg BID in those who met two of three clinical criteria (ABC-criteria). In AVERROES, apixaban proved to be more effective at preventing the composite of stroke and systemic embolism events (S/SEE) than aspirin and did not result in more major bleeding, whereas in ARISTOTLE it was both more effective and safer than warfarin. Several years after the adoption of apixaban in clinical practice, descriptive studies report that the rates of both thromboembolic and bleeding events in clinical practice are markedly higher than in the randomised trials (e.g. rate of events per patient-year for: ischaemic stroke [IS]: ~1.2% vs ~4.7% and intracranial haemorrhage [ICH]: 0.35% vs 0.76%). The reason for this increased rate of events is unknown but is likely related to the higher baseline risk of stroke and bleeding of patients taking apixaban in clinical practice compared with those enrolled in the randomised clinical trials (RCTs). It is possible, however, that greater variability in drug levels also contributed to the higher event rates in patients included in observational studies. Such a notion is plausible, because some of the clinical characteristics that increase the risk of stroke or bleeding also predispose to either reduced clearance or increased clearance of apixaban, thereby predisposing to both high and low levels of apixaban respectively. In addition, there was a greater tendency to prescribe the lower dose of apixaban (2.5 mg BID) in clinical practice which could therefore predispose to more low levels of apixaban. If, in truth, more frequent extremes in drug levels are contributing to the elevated event rates, it is possible that either or both refinements of the ABC-criteria or dose adjustments based on measured drug levels can improve outcome.
To investigate the contribution of extremes in drug levels, we compared drug levels from AVERROES (n = 2,392) with those from an observational study, the Apixaban Variability Study ([AVS]; n = 82), and determined the proportion of patients in AVS with a drug level within the lowest or highest deciles levels observed in AVERROES.
The results of our analyses showed that only 1.2% (95% confidence interval [95% CI]: < 0.01% - 7.24%) of patients in AVS had a drug level in the extremes based on the first and last deciles of drug levels in AVERROES.
We therefore conclude that the elevated rates of events observed in clinical practice are highly unlikely to be contributed by a greater prevalence of extremes in drug level.

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