We read with interest the study by Benzon et al.  1regarding international normalized ratio (INR) levels, epidural catheter removal, and guidelines developed by the American Society of Regional Anesthesia and Pain Medicine (ASRA). In summary, the authors evaluated the factor VII activities and INR in 121 patients during the initiation of warfarin therapy. Warfarin therapy was started the night of surgery; no additional antiplatelet or anticoagulants, including low-molecular-weight heparin, were administered. The authors reported that on postoperative day (POD) 1, 11 patients had prothrombin times greater than the 1.4 level recommended by ASRA for removal of an epidural catheter.2–4In 8 of these 11 patients, despite an increased INR, the factor VII activity levels were within the normal range. In the remaining 3 patients, the factor activities were 45%, 24%, and 22%, corresponding to INRs of 1.5, 1.5, and 1.8. Based on these results, Benzon and coworkers concluded that, for patients receiving epidural analgesia and warfarin for deep vein thrombosis prophylaxis, there is “no evidence that epidural catheters should not be removed even with INRs up to 1.9.”

Unfortunately, such a conclusion cannot be supported by their data, because their study did not directly test this hypothesis. Specifically, none of the 121 patients included in their retrospective study had an epidural catheter removed with a concurrent INR of 1.5–1.9. Consequently, the rate of epidural hematoma after epidural catheter removal at this intensity of anticoagulation cannot be estimated from this study, and it is impossible to conclude that such a practice is safe. Moreover, it is unclear from the data presented whether any of these patients even had an epidural catheter in place. If  epidural catheters were indwelling, catheter management, including the duration of epidural catheterization, factor VII activity, and INR at the time of catheter removal are critical to interpretation of the results.

The ASRA recommendation that epidural catheters be removed with the INR ≤ 1.4 was derived from studies correlating normal or near normal hemostasis with clotting factor activities greater than 40%. Benzon et al.  draw attention to the eight of eleven patients on POD 1 with INRs more than 1.4 and normal factor VII activity levels, citing the potential for unnecessary epidural catheter retention and discontinuation of warfarin therapy (until the INR ≤ 1.4) as their practice has established to be consonant with the ASRA guidelines. However, they do not address the issue of potential spinal hematoma in the two patients with an INR more than 1.4 on postoperative day 1 who had factor VII activities that were reduced sufficiently (24% and 22%, respectively) to increase the risk of bleeding with an invasive procedure. We question whether anesthesiologists would feel comfortable in removing an epidural catheter with an INR between 1.5–1.9 when almost 20% of such patients are potentially at an increased risk of bleeding.

Conversely, of the 110 patients with INRs ≤ 1.4 on POD 1, none  of the factor VII levels were below 40%, supporting the ASRA guideline of 1.4 as an appropriate cut-off value.

Importantly, Benzon et al.  1(and the “What This Article Tells Us That Is New” journal highlight) do not emphasize that their recommendation to remove an epidural catheter with an INR greater than 1.4 (and as high as 1.9) pertains solely to POD 1, when the INR reflects primarily a reduction of factor VII. With additional doses and time, an INR greater than 1.4 is typically associated with factor VII activity less than 40% (and the potential for inadequate clotting).5As Benzon et al.  noted, “… The INR represents the activity of several coagulation factors during the onset and the steady state of warfarin therapy.” Thus, it is imperative that not only the INR but also the duration of warfarin therapy be considered. Notably, many patients receive a preoperative  dose; their INR on POD 1 would represent 48 h of warfarin therapy.6Spinal hematomas have been reported in patients with INRs of 1.6 (48 h postoperatively) and 1.7 (72 h postoperatively).4 

ASRA has consistently recommended that epidural catheters be removed with an INR less than 1.5, recognizing also that “the management of patients receiving warfarin perioperatively remains controversial.”2–4Currently there are no laboratory assays that adequately assess the risk of bleeding with an invasive procedure7nor studies directly testing the safety of epidural catheter removal at a certain INR level. Certainly, this new body of information is relevant in establishing the boundaries of the controversy. Irrefutably, an INR of less than 1.4 should be considered safe for epidural catheter removal. Most likely, removing an epidural catheter within 12 h of initiation of warfarin therapy is safe in most patients. Benzon et al.  respect the variability and the hazard in concluding “… it is probably [emphasis added] safe to remove the epidural catheter in the first postoperative day of treatment, despite an increase in INR up to 1.9 …”1Unfortunately, a study of 121 patients with 2% incidence of potentially devastatingly low factor VII levels does not prove irrefutably a safe margin.

Epidural catheters have been uneventfully removed with an INR more than 1.4.8If this occurs early in the initiation of warfarin therapy, there probably are  adequate factor activity levels. Unfortunately, without measuring these levels (a process that may be appropriate on a case-by-case basis), it is impossible to know. Given the potentially catastrophic consequences of an epidural hematoma and the lack of definitive data, ASRA errs on the side of patient safety and recommends a more conservative timing of catheter removal. This value is also recommended by the American College of Chest Physicians,6the Belgian Association for Regional Anesthesia,9and the German Society for Anaesthesiology and Intensive Care Medicine.10 

Finally, given the narrow therapeutic range with warfarin and the high patient variability in warfarin response, inevitably there will be patients with an indwelling epidural catheter and an INR more than 1.4. Contrary to Benzon et al. 's interpretation, ASRA has never recommended that warfarin be routinely  held in any patient with an INR more than 1.4 and the epidural catheter removed only after the INR decreases to less than 1.5; this recommendation applied only to patients with INRs more than 3.2–4Routinely holding warfarin, as Benzon et al.  1note, places the patient at risk for thromboembolism. This is specifically addressed in The Third Edition of the ASRA Evidence-Based Guidelines4: “In patients with INR greater than 1.5 but less than 3, we recommend that removal of indwelling catheters should be done with caution and the medication record reviewed for other medications that may influence hemostasis that may not affect the INR. We also recommend that neurologic status be assessed before catheter removal and continued until the INR has stabilized at the desired prophylaxis level.”

We appreciate the efforts of Benzon et al.  to further define the safe practice of neuraxial block in patients receiving warfarin for thromboprophylaxis. However, the additional information presented does not contradict and actually supports the ASRA guidelines. We acknowledge that variances from the recommendations are acceptable based on the judgment of the responsible anesthesiologist and that there are times when the clinical situation will warrant the removal of an epidural catheter in a patient with an INR more than 1.4. Finally, these recommendations are certainly subject to timely revision. We hope the cautionary tone of this letter will serve to advise our colleagues that we are still waiting for more definitive data. Until then, close communication between the primary surgical service and the anesthesiology/acute pain/regional team is needed to provide patient care that achieves the highest quality and outcome and the safest practice.

*Mayo Clinic, Rochester, Minnesota. horlocker.terese@mayo.edu

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