Highlights
- The DALI study found that 7.6% of patients following standardized interruption protocols had residual direct oral anticoagulant (DOAC) levels of 30 ng/mL or higher at the time of elective surgery.
- Patients treated with apixaban were significantly more likely to have elevated preprocedural levels (13.1%) compared to those on rivaroxaban or dabigatran.
- Decreased kidney function and shorter interruption times were identified as key independent factors associated with higher residual DOAC concentrations.
- Crucially, preoperative DOAC levels were not associated with surgical blood loss, and all major bleeding events occurred in patients with levels below 30 ng/mL.
Background: The Challenge of Preoperative DOAC Management
The management of direct oral anticoagulants (DOACs)—including apixaban, rivaroxaban, and dabigatran—in the perioperative period is a critical concern for clinicians. Unlike warfarin, DOACs have a predictable rapid onset and offset, which has led to the development of standardized interruption protocols that typically do not require laboratory monitoring. The current gold standard for many centers involves discontinuing the drug 24 hours before moderate-risk procedures and 48 hours before high-risk procedures, with adjustments for renal function.
However, clinical anxiety remains regarding whether these fixed-time intervals ensure safe drug clearance. The threshold of 30 ng/mL is often cited as a conservative level below which the risk of anticoagulant-related bleeding is minimized, a figure largely derived from the landmark PAUSE trial. Despite these guidelines, real-world data on the actual drug concentrations present at the moment of surgical incision have been limited. The DOAC Level Prior to Incision (DALI) study was designed to address this gap by quantifying residual DOAC levels and assessing their clinical impact on surgical outcomes.
The DALI Study: Evaluating Current Interruption Protocols
The DALI study was a prospective cohort study conducted at two Dutch hospitals between May 2018 and February 2024. The researchers enrolled adult patients who were prescribed a DOAC for any indication and were scheduled for an elective procedure requiring medication interruption. The protocol followed established guidelines: a 1-day interruption for moderate-bleeding-risk procedures and a 2-day interruption for high-risk procedures, with specific extensions for patients with reduced creatinine clearance.
The primary objective was to estimate the proportion of patients with elevated DOAC levels (≥30 ng/mL) at the time of incision. To ensure high precision, drug levels were measured using liquid chromatography-mass spectrometry (LC-MS), the reference standard for DOAC quantification. The study also examined surgical blood loss and 30-day postoperative complications, providing a comprehensive look at the relationship between pharmacokinetics and clinical safety.
Key Findings: Residual Levels and Patient Factors
The study included 257 patients (100 receiving apixaban, 100 receiving rivaroxaban, and 57 receiving dabigatran). The median age was 72 years, and 82% of the participants underwent high-bleeding-risk operations, such as major orthopedic or abdominal surgeries. The results provided several nuanced insights into DOAC clearance.
The 30 ng/mL Threshold
Overall, 7.6% of the cohort had preprocedural DOAC levels of 30 ng/mL or higher. However, this risk was not distributed evenly across drug types. Among patients taking apixaban, 13.1% had levels above the threshold. In contrast, patients on dabigatran and rivaroxaban showed lower rates of residual elevation. This discrepancy suggests that apixaban may have a more variable clearance profile in elderly populations or those with specific comorbidities.
Predictors of Elevated Levels
Multivariable linear regression identified three primary factors associated with higher preprocedural DOAC levels: the specific use of apixaban, decreased kidney function (lower creatinine clearance), and shorter actual interruption times. While the protocol was adjusted for renal function, the findings suggest that the current adjustments may not fully account for the delayed clearance seen in patients with moderate renal impairment, particularly when combined with the pharmacokinetic properties of apixaban.
Clinical Implications: Does the DOAC Level Actually Predict Bleeding?
Perhaps the most striking finding of the DALI study was the lack of correlation between residual DOAC levels and surgical blood loss. The median blood loss was 0 mL, with a wide range reaching up to 4250 mL in complex cases. Statistical analysis confirmed that having a DOAC level ≥30 ng/mL did not independently predict increased intraoperative bleeding.
Furthermore, major bleeding complications within 30 days occurred in 12 patients (4.7%). Interestingly, all 12 of these patients had preprocedural DOAC levels below the 30 ng/mL threshold. This suggests that in the context of elective surgery, bleeding is more likely driven by surgical factors, patient-specific hemostatic variables, or the inherent complexity of the procedure rather than the residual concentration of the anticoagulant.
Expert Commentary and Methodological Considerations
The DALI study provides a measure of reassurance for clinicians using standardized interruption protocols. If over 92% of patients achieve the target level of <30 ng/mL, the protocols are largely performing as intended. However, the higher prevalence of residual apixaban levels raises important questions. Apixaban has a smaller volume of distribution and a different protein-binding profile compared to other DOACs, which might contribute to its persistence in some patients.
Clinicians should consider that while LC-MS is highly accurate, it is not always available in a rapid-turnaround format in all clinical settings. The study’s results suggest that routine preoperative monitoring may not be necessary for most patients, but a more personalized approach—perhaps adding an extra day of interruption for apixaban users with borderline renal function undergoing very high-risk surgery—could be considered.
It is also important to note the study’s limitations. The sample size for dabigatran was smaller due to slow recruitment, and the study was terminated early. While the findings on blood loss are compelling, the study may not have been powered to detect very small differences in bleeding risk associated with drug levels.
Conclusions for Clinical Practice
The DALI study reinforces the safety of current DOAC interruption guidelines for most patients. The primary takeaway for the surgical team is that a residual level slightly above 30 ng/mL does not appear to be a primary driver of surgical hemorrhage. Instead, the focus should remain on meticulous surgical technique and the management of other perioperative risk factors.
For patients on apixaban or those with significant renal impairment, clinicians should be aware that clearance may be slower than expected. While the study does not mandate a change in guidelines, it highlights the need for clinical vigilance and the potential benefit of adhering strictly to (or slightly extending) interruption windows in high-risk scenarios. As we move toward more personalized medicine, understanding these pharmacokinetic nuances will be essential for optimizing patient safety in the operating room.
