Nonsteroidal Antiinflammatory Drugs, Antiplatelet Medications, and Spinal Axis Anesthesia

Aspirin and Nonsteroidal Antiinflammatory Drugs

Aspirin is a commonly used medication that has many indications, including but not limited to coronary artery disease, stroke, stents, preeclampsia, and thromboprophylaxis. It inhibits platelet function by inhibiting COX, which is an enzyme necessary to synthesize thromboxane A2 from arachidonic acid. Thromboxane, a prostaglandin that causes platelet aggregation and adhesion, requires thromboxane A2 in its formation. COX exists in two forms; COX-1 regulates platelet aggregation, whereas COX-2 mediates pain and inflammation. Aspirin (60–325 mg) inhibits COX-1, and higher doses inhibit COX-2 as well. Inhibition of platelet function lasts for the life of the platelet, which is 7 to 10 days. The risk for bleeding is higher in higher doses than in low-dose aspirin.

NSAIDs such as naproxen, ketorolac, diclofenac, piroxicam, and ibuprofen are also COX-1 inhibitors, but they cause reversible platelet inhibition. This means that platelet function usually returns to normal within 1 to 3 days after discontinuing the drug. Selective COX2 inhibitors, however, such as celecoxib (Celebrex), are not expressed in platelet function and do not cause platelet dysfunction.

The ASRA considers the continued use of aspirin and NSAIDs to pose a minimal risk when conducting spinal axis analgesia/analgesia. The evidence for a risk for spinal/epidural hematoma formation if these medications are not stopped is quite sparse and is limited to case reports. Vandermeulen and colleagues, in their review of the literature from 1906 to 1993, were able to find only three cases in which an NSAID was implicated and only two cases related to aspirin use. One of these latter two cases also involved the concurrent use of heparin. ^, Nevertheless, more sporadic reports continue to emerge. Heye presents a patient who was taking 250 mg/day aspirin and developed an epidural hematoma after spinal trauma. Heye suggests that although aspirin did not cause the bleeding, it did have a major impact on the extent of the epidural bleeding. Hyderally describes a patient with ankylosing spondylitis who was undergoing total hip replacement and was started on aspirin for postoperative thromboprophylaxis. This patient subsequently developed a thoracic epidural hematoma 36 hours postoperatively. More importantly, this thoracic-level epidural hematoma extended from T5 to T10, which was quite distant from the lumbar epidural catheter tip, which, as confirmed by magnetic resonance imaging (MRI), was at L2/L3. Hyderally concluded that the lumbar epidural catheter placement did not cause the hematoma, but that it occurred spontaneously, possibly because of concurrent aspirin therapy and the patient’s primary disease of ankylosing spondylitis. Benzon et al. reported an epidural hematoma in a patient who had received multiple antiplatelet medications, including clopidogrel and aspirin. Another report comes from a patient who received an epidural steroid injection and was on 81 mg of aspirin. The patient developed an exacerbation of back pain after a period of relief, which was later found to be a hemorrhagic synovial mass emanating from either facet joint or ligamentum flavum with good outcome after surgical removal.

NSAIDs also continue to have their share of reports after the screening study by Vandermeulen et al., which spanned 87 years. Litz and colleagues implicate the perioperative administration of ibuprofen in the formation of a hematoma after epidural catheter removal; however, the patient was also receiving low-molecular-weight heparin (LMWH). Martinez Santos et al. describe a 29-year-old male on a high dose of naproxen (3000 mg per day) who developed a spontaneous spinal epidural hematoma spanning T1 to L5 with full neurologic recovery after surgical decompression. Similarly, Williams et al. describe a case that involved indomethacin in which the patient developed a cervical epidural hematoma after her seventh epidural injection.

Ketorolac was also implicated in several cases. Gerancher and colleagues describe a patient who received a spinal anesthetic; the patient did not receive any anticoagulation and only received a 30-mg dose of ketorolac during surgery followed by three 15-mg doses postoperatively. The patient developed a lumbar hematoma on the first postoperative day. Jeon et al. report a 26-year-old male on naftazone, mefenamic acid, and ketorolac who received a traumatic combined spinal-epidural (CSE) anesthesia and developed an epidural hematoma 5 days later. Platelet dysfunction was demonstrated on laboratory results, which could have been happening from medications the patient was taking around the time of the CSE. Chien et al. describe another case of epidural hematoma after cervical epidural steroid injection. The patient was receiving ketorolac, but the authors conclude that some other risk factors, such as chronic renal insufficiency and advanced age, may have contributed to the development of the epidural hematoma. The concurrent use of ketorolac and LMWH has been implicated in several cases of spinal/epidural hematomas. Uremey and Rowlingson reported three cases early on. Svelato et al. reported another case, in which the patient received a CSE anesthesia and was started postoperatively on dalteparin and ketorolac. On postoperative day 6, she complained of severe low back pain. This was 3 days after the epidural had been removed and 12 hours after the last dalteparin dose. It was later proven to be an epidural hematoma.

Despite the aforementioned reports, there are a few studies that reported no harm from placing neuraxis anesthesia/analgesia while using aspirin and NSAIDs. A literature review by Moeschler et al. in patients with a spinal cord stimulator revealed no cases of epidural hematomas. It looked retrospectively at 642 patients from 2005 through 2014 and found more than 100 patients receiving aspirin or NSAIDs. Similarly, Horlocker and colleagues ^, and Urmey and Rowlingson all believe that there was a minimal risk for spinal/epidural hematoma formation when perioperative aspirin or another COX-1 inhibitor NSAID were administered with neuraxial anesthesia. Horlocker and colleagues also retrospectively reviewed 805 charts of patients receiving NSAIDs who were administered a neuraxis anesthetic. None of the patients developed a spinal hematoma in the postoperative period. Horlocker et al. also prospectively studied 924 patients who received 1000 spinal or epidural anesthetics. Of these patients, 386 (39%) were taking aspirin ( n = 193), and the remaining 193 patients were taking another COX-1 inhibitor NSAID. Moreover, 32 patients in this latter group were taking more than one NSAID in the preoperative period. Blood was noted during needle or catheter placement (minor hemorrhagic complications) in 223 of the patients (22%), including 73 who had frank blood in either their needle or catheter. None of the patients developed a spinal hematoma in the postoperative period. In another study by Horlocker and colleagues that involved 1035 patients who received 1214 epidural steroid injections, 383 of the 1035 patients (32%) were concurrently taking an NSAID. More specifically, 158 of these 383 patients consumed aspirin, and 104 of the 158 were using low-dose aspirin (325 mg/day or less). The authors conclude that epidural steroid injection is safe in patients receiving either aspirin or NSAIDs. Table 37.1 shows the combined results of the three Horlocker studies. Most critics of this article argue that a more extensive review needs to be done to change the current guidelines safely. Horlocker et al., however, recommend “against the concurrent use of medications that affect other components of the clotting mechanisms and may increase the risk of bleeding complications (and include) aspirin and other NSAIDS,” which is no change in this recommendation from the previous guidelines.

APD Inhibitors: Thienopyridines

The thienopyridine-based APD inhibitors include ticlopidine, clopidogrel, and prasugrel.

Ticlopidine (Ticlid)

Ticlopidine is a long-lasting inhibitor of both primary and secondary phases of platelet aggregation. ^, Its effect is irreversible and lasts for the lifetime of the platelet. Currently, ticlopidine is discontinued from the market because of its bone marrow toxicity. It has been implicated in two cases of a spinal hematoma; one of them was spontaneous. ^,

The current ASRA guidelines recommend that ticlopidine be stopped 10 days before surgery instead of 14 days, as in the previous guidelines. Nevertheless, because the antiplatelet effect is not immediate with ticlopidine, neuraxial catheters may be maintained for 1 to 2 days, provided a loading dose of the antiplatelet agent is not administered.

Clopidogrel (Plavix)

Clopidogrel’s antiplatelet effect is slow in onset and highly variable. The onset of the antiplatelet effect of a single 75-mg dose is 12 to 24 hours after administration. On the other hand, loading with a 600-mg dose achieves comparable platelet aggregation inhibition within 8 hours. The maximum platelet inhibition effect of clopidogrel 75 mg/day is observed after 4 to 5 days, and this delay is because of its need for metabolic activation. Its irreversible platelet inhibition persists for several days after withdrawal of the drug and diminishes in proportion to platelet renewal. It is important to note, however, that the antiplatelet effect of clopidogrel is not consistent in all patients and that up to 30% of patients have marked variability in the extent of platelet inhibition. Furthermore, it is noted that up to 5% to 15% of high-risk patients with acute coronary syndrome have further ischemic events despite adequate antiplatelet therapy with clopidogrel. The reason for this variability seems to be because clopidogrel is a prodrug and must be metabolized before it can bind to ADP receptors and inhibit platelet aggregation. Studies have shown that the CYP450 enzyme’s genetic variations result in a reduction in enzymatic activity associated with decreased activation of the drug, resulting in lessened antiplatelet inhibition and an increased likelihood of cardiovascular events. ^, The reduced responsiveness to clopidogrel is also related to some medical conditions like diabetes mellitus and obesity.

Clopidogrel was implicated in two cervical epidural hematomas after cervical epidural steroid injection for pain management. In one of the cases the patient took several antiplatelet medications just before the block placement (diclofenac, clopidogrel, and aspirin), and the other one happened 12 days after discontinuing clopidogrel.

Delayed-onset hematomas after stopping clopidogrel for an adequate period have been reported as well. One happened 10 days after a lumbar drain removal in the setting of vascular surgery and in combination with other antithrombotic medications. The patient was started on 75 mg clopidogrel daily, subcutaneous heparin, and aspirin 24 hours after the lumbar drain placement; the lumbar drain was removed on postoperative day 3 and within 48 hours of initiating antiplatelet therapy. During the period of the lumbar drain presence, the patient was symptom-free, with clear cerebrospinal fluid. The epidural hematoma occurred several days after the removal of the lumbar drain and may have been related to the clopidogrel reaching therapeutic levels at that time or may have been the development of a spontaneous epidural hematoma. Another case occurred in a patient who had his clopidogrel held for 7 days preoperatively before receiving a CSE. The only anticoagulant the patient received was a LMWH dalteparin as directed by the guidelines. Although the aforementioned cases happened in the setting of a neuraxis procedure, it is noteworthy that there are multiple case reports of spontaneous epidural hematomas in the literature in which clopidogrel was implicated with or without other antithrombotic medications. ^,

Despite the fact that the current recommendations consider maintaining a catheter for 1 to 2 days after the start of clopidogrel, a case of an epidural hematoma was reported after a single 75-mg dose of clopidogrel was administered 30 hours before the epidural catheter removal. The patient had their preoperative clopidogrel withheld 7 days before surgery while they continued their daily aspirin. At the time of the catheter removal, the subcutaneous heparin was held for 8 hours.

In contrast, some case series argue that the perioperative use of clopidogrel in the setting of placing and maintaining an epidural catheter is not an issue. Osta et al. reported placing epidural analgesia on 306 vascular surgical patients with no harm. The perioperative clopidogrel was only held for 24 hours before surgery. All patients received frequent neurologic checks for 72 hours or until discharge. The study was criticized for its small sample size, its retrospective nature, and exposing the patients to the risk of developing an epidural hematoma by not following the guidelines. Hodgson et al. state that “306 patients only means that the incidence of such a hematoma is probably less than 1:102, hardly reassuring, and certainly insufficient to overturn the ASRA recommendations.” Similarly, another retrospective case-control study looked into 2469 patients. The patients underwent transforaminal epidural steroid injections and were on different types of antithrombotic medications. These medications included warfarin, heparin, aspirin, clopidogrel, and limaprost (Opalmon). The patients were divided into three groups. One group discontinued the antithrombotic medications (n = 1234), the second group patients continued them (n = 408), and the third group (n = 827) did not use any. The study concluded that the continued use of the antithrombotic medications did not increase the risk for epidural hematoma and thus should not be considered a contraindication for transforaminal epidural steroid injections. Still, this study was underpowered and did not take the safety of the patients seriously. Another small retrospective review by neurology researchers identified 100 patients who underwent lumbar puncture (LP) while taking aspirin and clopidogrel and followed them for 3 months. They recorded no epidural hematoma cases or serious complications. Nevertheless, some of them had a traumatic puncture and so the authors concluded that one could reasonably proceed if a patient is on dual antiplatelet therapy.

ASRA Recommendations for Clopidogrel