The main results of our study are the following: 82.2% of AF patients admitted to the hospital for elective cardiac procedure showed DOAC plasma levels out of the therapeutic trough range (41.1% below and 41.1% above). Creatinine clearance > 95 ml/min and the inappropriate longer drug withdrawal period are the only independent predictors of DOAC plasma levels below the reference range; in contrast, diabetes significantly correlated with DOAC plasma levels above the reference range.

According to the current recommendations, the correct timing of DOAC discontinuation before elective surgery depends on the patients’ clearance of creatinine, evaluated by Cockcroft-Gault formula, and on the hemorrhagic risk of the interventional procedure [2]. Many elective cardiac procedures are considered at minor hemorrhagic risk, carrying infrequent bleedings and with low clinical impact, and may be performed under minimally- or uninterrupted DOAC therapy (i.e., 12–24 h after last intake) [2]. This approach is based on DOAC pharmacokinetics and leads to perform the procedure at trough DOAC plasma level [7]. The management of DOACs may be challenging in several clinical scenarios or special populations and needs to be carefully evaluated [8]. Actually, few studies evaluated the DOAC plasma levels among AF patients in need of elective surgery [9].

In a sub-analysis of the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study, Shaw et al. [10] evaluated prespecified periprocedural-interruption strategy of DOACs among 2541 AF patients. A cut-off < 30 ng/mL, 30–49.9 ng/mL, and 50 ng/mL is empirically classified as undetectable or negligible, mildly elevated, and moderately elevated, respectively. Of the study patients, 79.4% showed preprocedural DOACs values considered safe (< 30 ng/mL). Among patients undergoing low-risk procedures, it was reported that age, female sex, use of a standard dose of DOACs, and a shorter DOAC discontinuation were associated with values > 30 ng/mL. Among patients in need of high-risk procedures, only weight and clearance were associated with DOAC levels > 30 ng/mL.

In a multicenter observational study including 422 patients who were taking DOACs, either for AF or venous thromboembolism (VTE), Godier et al. [11] aimed to determine the optimal duration of DOAC discontinuation that ensures a minimal anticoagulant effect at the day of invasive procedure (either elective or urgent). Applying the optimal DOAC discontinuation with a last DOAC intake 3 days before procedure, 77% of the study population achieved a minimal preprocedural DOAC plasma level ≤ 30 ng/mL. The duration of DOAC discontinuation, creatinine clearance < 50 mL/min, and antiarrhythmics were independent predictors of minimal preprocedural. Lastly, creatinine clearance < 50 mL/min, antiplatelets, and high-bleeding risk procedures were predictors of bleeding events.

Different from the previous studies [10, 11], we used, as reference ranges to classify the study population, the peak and trough serum levels specific for each type and dosage of DOACs. Moreover, we considered the discontinuation time suggested by the European Heart Rhythm Association (EHRA) recommendations to evaluate the withdrawal period as appropriate or inappropriate (longer or shorter).

Our results confirmed the relationship between creatinine clearance and DOAC plasma levels, since the increased creatinine clearance, in particular when it was higher than 95 ml/min, seems to be associated with DOAC plasma levels below the reference range. As expected, also the inappropriate longer drug withdrawal period was significantly correlated to it. Moreover, we firstly showed that diabetes may be associated with DOAC plasma levels above the reference range. Our speculative hypothesis is that this association may be mediated by the oxidative stress, a significant factor in the development and progression of diabetes [12], which may modulate the activity of both cytochrome (CYP) enzymes and glycoprotein (P-gp). In particular, the increased oxidative stress can inhibit the activity of CYP enzymes [13], leading to the altered metabolism and clearance of DOACs; moreover, it can modulate the activity of P-gp [14], affecting the efflux of DOACs from cells. The oxidative stress–induced modifications may potentially lead to the increased DOAC plasma levels among diabetic patients.

Finally, regarding the optimal DOAC withdrawal period before cardiac elective procedure, our results support the strategy suggested by EHRA recommendations based on the bleeding risk related to the procedure and the patient’s creatinine clearance. In case of diabetic patients, our results suggest that preprocedural DOAC plasma dosing might be part of a more careful patient-centered evaluation, especially in those with several risk factors for bleeding or undergoing procedures at high hemorrhagic risk.

Our study is limited by the relatively small number of patients; indeed, this is a single-center study reflecting the local practice and the generalization of results is limited. However, it is the only real-world observational study which included AF patients in need of elective cardiac procedures evaluated by DOAC plasma dosing and in whom the reference ranges are DOACs-specific and the withdrawal periods are not arbitrary. Moreover, we did not use high-performance liquid chromatography-mass spectrometry (HPLC/MS), currently considered the gold standard method for DOAC quantification; however, the assays used in our study provide drug measurements comparable to those measured with HPLC/MS [8].