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Regional Anesthesia in the Anticoagulated Patient
AUTHOR: Honorio T. Benzon
The incidence of intraspinal hematoma is approximately 0.1 per 100,000 patients per year.(1) It is more likely to occur in anticoagulated or thrombocytopenic patients, patients with neoplastic disease, or in those with liver disease or alcoholism.(2) The incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is estimated to be
Antiplatelet medications inhibit platelet cyclo-oxygenase and prevent the synthesis of thromboxane A2. Thromboxane A2 is a potent vasoconstrictor and facilitates secondary platelet aggregation and release reactions. An adequate, although potentially fragile, clot may form.(5) Platelet function in patients receiving antiplatelet medications should be assumed to be decreased for 1 week after treatment with aspirin and 1 to 3 days with nonsteroidal anti-inflammatory drugs (NSAIDs). New platelets are produced every day, and these new platelets partly explain the relative safety of per- forming neuraxial procedures in these patients.
Although Vandermeulen et al (6) implicated antiplatelet therapy in 3 of the 61 cases of spinal hematoma occurring after spinal or epidural anesthesia, the results of several large studies demonstrated the relative safety of neuraxial blockade in combination with antiplatelet therapy. The Collaborative Low-Dose Aspirin Study in Pregnancy Group(7) included 1422 high-risk obstetric patients who were administered 60 mg aspirin daily and underwent epidural anesthesia without any neurologic sequelae. The studies of Horlocker et al,(8,9) of approximately 1000 patients in each study, showed no spinal hematomas, although blood was noted during needle or catheter placement in 22% of the patients. A later study in patients who were on NSAIDs and underwent epidural steroid injections did not develop the signs and symptoms of intraspinal hematoma.(10) A review of the case reports of intraspinal hematoma in patients on aspirin and NSAIDs showed complicating factors that in luded concomitant heparin administration, epidural venous angioma, and technical difficulty when performing the procedure.(11)
The thienopyridine drugs, ticlopidine and clopidogrel, prevent platelet aggregation by inhibiting adenosine diphosphate (ADP) receptor-mediated platelet activation. Ticlopidine is rarely used because it causes neutropenia, thrombocytopenic purpura, and hypercholesterolemia. Clopidogrel is preferred because of its increased safety profile and proven efficacy. The maximal inhibition of ADP-induced platelet aggregation with clopidogrel occurs 3 to 5 days after the initiation of a standard dose (75 mg), but within 4 to 6 hours after the administration of a large loading dose of 300 to 600 mg.(12) There is a case report of spinal hematoma in a patient on ticlopidine(13) and a case of quadriplegia in a patient on clopidogrel, diclofenac, and possibly aspirin.(14)
Neuraxial blocks can be safely performed on patients taking aspirin or NSAIDs.(4) It is safe to perform neuraxial blocks on patients taking cyclo-oxygenase (COX)-2 inhibitors. For the thienopyridine drugs, it is recommended that clopidogrel be discontinued for 7 days and ticlopidine for 10 to 14 days before a neuraxial injection. It is possible for epidural catheters to be removed or neuraxial injections to be performed 5 days, and not 7 days, after clopidogrel is discontinued.(15) If a neuraxial injection is to be performed in a patient on clopidogrel before 7 days of discontinuation, a P2Y12 assay, a new assay of residual antiplatelet activity, can be performed;
Here is a summary of current recommendations:
1. Neuraxial blocks can be performed on patients taking aspirin or NSAIDs.(4)
2. It is safe to perform neuraxial blocks on patients taking COX-2 inhibitors.
3. For the thienopyridine drugs, the ASRA recommendation is that clopidogrel be discontinued for 7 days and ticlopidine for 10 to 14 days before a neuraxial injection.
4. Epidural catheters can be removed safely and neuraxial injections can be performed 5 days (not 7 days, as once advised) after clopidogrel is discontinued.(15)
5. If a neuraxial injection is to be performed in a patient on clopidogrel before 7 days of discontinuation, a P2Y12 assay, a new assay of residual antiplatelet activity, is performed;
Warfarin exerts its anticoagulant effect by interfering with the synthesis of the vitamin K-dependent clotting factors (VII, IX, X, and thrombin).17 It also inhibits the anticoagulants protein C and S. Factor VII and protein C have short half-lives (6-8 hours), and the prolongation of the international normalized ratio (INR) during the early phase of warfarin therapy is the result of the competing effects of reduced factor VII and protein C.(18) Adequate anticoagulation is not achieved until the levels of biologically active factors II (half-life of 50 hours) and X are sufficiently depressed, that is, 4 to 6 days.
Few data exist regarding the risk of spinal hematoma in patients with indwelling spinal or epidural catheters who are subsequently anticoagulated with warfarin. Horlocker et al(19) and Wu and Perkins(20) found no neuraxial hemorrhagic complications in patients who received postoperative epidural analgesia in conjunction with low-dose warfarin after total knee arthroplasty. Because intraspinal hematomas have occurred after removal of the catheter,(6) some have recommended that the same laboratory values apply to placement and removal of an epidural catheter.(21) The current ASRA guidelines recommends an INR value of ≤1.4 as acceptable for the performance of neuraxial blocks.(4) The value was based on studies that showed excellent perioperative hemostasis when the INR value was ≤1.5. The concurrent use of other medications, such as aspirin, NSAIDs, and heparins that affect the clotting mechanism, increases the risk of bleeding complications without affecting the INR.
A controversy exists regarding whether or not the epidural catheter can be removed on postoperative day 1, or 12-14 hours after warfarin is started, when the INR is >1.4. In the absence of other risk factors for increased bleeding, the catheter can probably be removed. The factor VII activity should be determined if risk factors such as low platelets, advanced age, kidney failure, or intake of other anticoagulants are present.(18)
Warfarin is metabolized primarily by the CYP2C9 enzyme of the cytochrome P450 system. Mutations in the gene coding for the cytochrome P450 2C9 hepatic microsomal enzyme affect the elimination clearance of warfarin by impairing the patient’s ability to metabolize S-warfarin. Other genetic factors affecting the warfarin dose-response relationship include polymorphisms of the vitamin K oxide reductase (VKOR) enzyme. Mutations in the gene encoding for isoforms of the protein that can lead to enzymes with varied sensitivities to warfarin is rare, and the American College of Chest Physicians (ACCP) advises against pharmacokinetic-based initial dosing of warfarin at this time.(17)