Complications related to venous thromboembolism (VTE) after major spinal surgery can be considerable and interrelate with neurologic deficits and a number of other risk factors, such as delay in mobilization of patients and comorbidities. This has led to the perceived benefit of anticoagulation therapy after spinal surgery because of these postoperative risks, which can predispose the patient to deep vein thrombosis (DVT) and pulmonary embolism (PE) and lead to medical morbidity or mortality. The perceived benefit of anticoagulation after spinal surgery is further bolstered by the notion that DVT and PE after surgery are preventable complications, as noted by inclusion onto the Center for Medicare and Medicaid Services “never events” list for complications that Center for Medicare and Medicaid Services will no longer pay for under the fiscal year 2009 inpatient prospective payment system final rule. Further guidelines have been created by the American Academy of Orthopedic Surgeons and the American College of Chest Physicians that specify the use of chemical prophylaxis in specific groups of postoperative patients.1
There is, however, a plausible concern that anticoagulant use after spine surgery may induce symptomatic postoperative hematoma formation and lead to secondary neurologic deficits (Figure 3). On general review, there seemed to be a paucity of literature on this topic. The purpose of this systematic review is to attempt to answer the following 3 clinical questions:
- What are the high-risk populations for thromboembolic events in spine surgery patients?
- What is the defined risk of anticoagulation in spine surgery patients by type of anticoagulation?
- Is there a safe perioperative window of nonanticoagulation for these high-risk patients?
Materials and Methods
Electronic Literature Database
The literature search is outlined in detail elsewhere.1a We conducted a systematic search in Medline, EMBASE, and the Cochrane Collaboration Library for literature published from January 1979 through December 2008. We limited our results to humans and to articles published in the English language. Reference lists of key articles were also systematically checked.
We excluded studies evaluating surgical interventions that involved nonspine orthopedic injuries. In addition, we did not include studies involving spinal cord injury. For our first study question, we attempted to identify studies specifically designed to evaluate the incidence or frequency of thromboembolic events after spine surgery for various spinal conditions. We included prospective and retrospective studies whose purpose was to document thromboembolic events determined by venography, ultrasonography, Doppler imaging or fibrinogen uptake test for DVT, and by lung perfusion scans or imaging studies for PE. To determine the risk of anticoagulation in spine surgery patients (study question no. 2), we attempted to identify studies that specifically evaluated bleeding outcomes in patients given chemical prophylaxis. To determine a safe perioperative window of nonanticoagulation for these high-risk patients (study question no. 3), we attempted to identify studies that measured the effect of an intervention or prevention strategy. We excluded editorials, review articles without quantitative data, case reports, and non-English-written studies (Figure 1).
Each retrieved citation was reviewed by 2 independent reviewers (J.R.D. and D.F.). Most articles were excluded on the basis of information provided by the title or abstract. Citations that seemed to be appropriate or those that could not be excluded unequivocally from the title and abstract were identified, and the corresponding full-text reports were reviewed by the 2 reviewers. Any disagreement between them was resolved by consensus. From the included articles, the following data were extracted: study design, patient demographics, diagnosis, surgical treatment rendered, antithrombotic prophylaxis administered, rate or number of documented events of thromboembolic events, and outcomes of this complication.
Level of evidence ratings was assigned to each article independently by 2 reviewers using the criteria established by The Journal of Bone and Joint Surgery, American Volume (J Bone Joint Surg Am)2 for therapeutic and prognostic studies, and modified to delineate criteria associated with methodologic quality and described elsewhere (See Supplemental Digital Content 1, individual study ratings, tables, individual study ratings, available at: http://links.lww.com/BRS/A419).
The risk of a thromboembolic event was reported as the proportion of patients experiencing either a DVT, PE, or death as a result of PE after spine surgery, who received no chemical antithromboembolic prophylaxis. The risk of bleeding was reported as the proportion of patients experiencing bleeding or hematoma who received antithromboembolic prophylaxis. Data were summarized in tables and qualitative analysis was performed considering the following 3 domains: quality of studies (level of evidence), quantity of studies (the number of published studies similar in patient population, condition treated, and outcome assessed), and consistency of results across studies (whether the results of the different studies lead to a similar conclusion).3 We judged whether the body of literature represented a minimum standard for each of the 3 domains using the following criteria: for study quality, at least 80% of the studies reported needed to be rated as a level of evidence I or II; for study quantity, at least 3 published studies were needed, which were adequately powered to answer the study question; and for study consistency, at least 70% of the studies had to have consistent results. The overall strength of the body of literature was expressed in terms of the impact that further research may have on the results. An overall strength of “high” means that further research is very unlikely to change our confidence in the estimate of effect. The overall strength of “moderate” is interpreted as further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. A grade of “low” means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, whereas “very low” means that any estimate of effect is very uncertain.1a
We identified 93 articles or reports from our literature search reporting on thromboembolic events or significant hemorrhage (secondary to anticoagulant use). From these potential articles or reports, we judged 41 to undergo full-text review. After full-text review, we excluded 12 for the following reasons: 6 studies did not meet the inclusion criteria (included nonspinal groups), and 6 studies did not report data on the outcomes of interest (Figure 2). Of the remaining 29 articles, 15 provided information on the incidence of thromboembolic events in patients who had no chemical prophylaxis (study question no. 1) and 7 provided information on the risk of bleeding complications in spine surgery patients receiving anticoagulation prophylaxis (study question no. 2) (Supplemental Digital Content, available at: http://links.lww.com/BRS/A419; demographic information for these studies is recorded in Table 1). Seven studies did not indicate whether chemical antithrombotic prophylaxis was given4–9,10 (Supplemental Digital Content, available at: http://links.lww.com/BRS/A419; these studies are summarized separately in Table 2).
Among the studies presenting data on the incidence of thromboembolic events after spine surgery in patients without chemical antithrombotic prophylaxis, 10 are prospective cohort studies, 1 was graded as level of evidence I11 and 9 graded as level of evidence II,12–20 4 are retrospective cohort studies graded as level of evidence III,21–24 and 1 is a prospective and retrospective cohort study graded as level of evidence II–III.25 We found 7 articles evaluating the risk of bleeding complications in spine surgery patients receiving anticoagulation therapy. Of these, 6 are prospective studies graded as level of evidence II16,26–30 and 1 retrospective cohort study graded as level of evidence III31 (Supplemental Digital Content, available at: http://links.lww.com/BRS/A419; further details for each study can be found in Tables 3 and 4).
Question 1. What Are the High-Risk Populations for Thromboembolic Events in Spine Surgery Patients?
Several studies attempted to identify spinal conditions that may contribute to an increased risk of thromboembolic events in spine surgery. In general, studies of spine surgery reported the proportion of patients who had complications of DVT, PE, and fatal outcomes associated with PE. Fifteen studies reported frequencies of thromboembolism among patients who did not receive pharmacologic antithrombotic prophylaxis (Table 1). The risk of thromboembolic complications tended to be higher in trauma and deformity patients than in patients treated for degenerative conditions. The risk of thromboembolism after spine surgery in nonspinal cord injury trauma patients in 2 studies was 6.0% (range, 0%–19%) for DVT and 2.0% (range, 0%–1.5%) for PE18,19; in patients with deformity in 3 studies, 5.3% (range, 2%–14%) for DVT and 2.7% (0%–7.6%) for PE18,19,21; and in patients with degenerative conditions in 7 studies, 2.3% (range, 0%–9%) for DVT and 0.4% (range, 0%–1.5%) for PE.13,15,20,22–25 Fatal PE was reported twice among the 14 studies; once in a trauma patient18 and once in a patient after an uneventful anterior stage of a combined lumbar anterior-posterior fusion for pseudarthrosis.25 In patients who received chemical antithrombotic prophylaxis, the rate of DVT was 0.0% to 4.6%, whereas PE was reported in 0.0% to 2.2% of patients (Table 2).
Question 2. What Is the Defined Risk of Anticoagulation After Spine Surgery by Type of Anticoagulation?
We identified 7 comparative studies that evaluated adverse events in 2 categories of anticoagulation: anticoagulants, which include fractionated and unfractionated heparin and Warfarin, or antiplatelet agents, which include aspirin, nonsteroidal anti-inflammatory agents, and Plavix.
The risk of bleeding from anticoagulant agents in spinal surgery in 5 prospective and 1 retrospective cohort study was small; risk of major bleeding ranged from 0.0% to 4.3% across several types of anticoagulants. Hematoma was reported in only 10 cases in 2507 patients (Table 2).
In a prospective study, Rokito et al26 assessed complications associated with anticoagulation methods in 110 patients who underwent major spine surgery. Patients were randomized to receive bilateral thigh-high thrombosis embolic deterrent (TED) compression stockings placed before surgery and worn until discharge (n = 42), TED stockings and thigh-length cuffs that provided sequential pneumatic compression to the calf and thigh (n = 33), or TED stockings and 10 mg Coumadin administered on the evening before surgery followed by daily Coumadin until duplex Doppler studies were obtained (fifth to seventh postoperative day) to maintain the prothrombin time level at 1.3 to 1.5 times control (n = 35). No bleeding complications were reported in the TED or TED and thigh-length cuff groups. In the Coumadin group, 1 patient experienced an excessive amount of drainage on postoperative day 1 (minor bleeding complication, 2.9%), and another experienced excessive intraoperative blood loss (major bleeding complication, 2.9%). Both of these patients required blood transfusions. No other adverse events were reported.
Another prospective study included 179 patients scheduled for surgical procedures because of a prolapsed lumbar-intervertebral disc.27 Individuals were randomized to receive either 32 mg low-molecular-weight heparin (LMWH) and 0.5 mg dihydroergotamine (DHE) once a day plus 1 placebo injection per day (LMWH/DHE; n = 87) or 5000 U unfractionated heparin plus 0.5 mg DHE (HDHE) twice a day (n = 92). The medication was administered 2 hours before the surgical procedure and every 12 hours for at least 7 days. Excessive intraoperative blood loss, determined via subject assessment of the surgeon, was observed in 0 (0.0%) patients receiving HDHE, and 4 (4.3%) in the LMWH/DHE group. Excessive postoperative loss of blood in drains (minor bleeding complication) was found in 8 (9.2%) treated with LMWH/DHE and 3 (3.3%) in the HDHE group. Five (5.7%) patients in the LMWH/DHE group required blood transfusions, whereas 4 (4.3%) who received HDHE required transfusions. No hematomas, deaths, or other adverse events were reported.
Gruber et al16 reported the results of a prospective study of 50 patients undergoing lumbar disc surgery. Patients were randomized to receive either 2500 IU HDHE twice daily (n = 25) or placebo (n = 25) beginning 2 hours before surgery and every 12 hours afterward for at least 7 days (if determined to be clinically necessary) or until discharge from the hospital. Intraoperative increased bleeding was determined via surgeon assessment. Six (24%) patients in the HDHE group and 7 (28%) in the placebo group experienced minor intraoperative increased bleeding. No major bleeding complications were reported in either group. One (4.0%) hematoma, which resolved spontaneously, was reported in the placebo group. No other adverse events were reported.
The use of the LMWH, Bemiparin, was studied in a prospective, multicenter cohort study by Otero-Fernandez et al.28 The authors enrolled 231 spine surgery patients into the study, who were planned to receive extended prophylaxes after their hospital stay. Patients received once-daily, subcutaneous administration of Bemiparin 3500 IU/day (high risk) or 2500 IU/day (moderate risk) for a median of 21 days. Major bleeding was defined as any bleeding in critical organs, fatal bleeding, bleeding requiring reoperation to control bleed, or any bleeding requiring treatment cessation. Minor bleeding was bleeding that did not meet criteria for major bleeding. In the 225 patients who completed the study, 0.89% (2 of 225) had a major bleeding episode and 3.56% (8 of 225) experienced a minor bleeding episode. No other adverse events were reported.
Schizas et al29 prospectively followed a consecutive cohort of 270 patients who underwent spinal surgery. Compressive stockings were used on all patients on admission. Enoxoparin was administered once daily starting during the eighth postoperative hour (20 mg for the first 3 postoperative days and 40 mg thereafter) and discontinued on discharge. Postoperative hematomas requiring surgical evacuation were recorded. Two (0.7%) patients developed postoperative hematomas requiring emergency evacuation. Neither patient developed neurologic signs or symptoms.
In 1 retrospective cohort study, Gerlach et al31 analyzed the rate of postoperative hemorrhage associated with early (<24 hours after surgery) postoperative daily administration of 0.3 mL of nadroparin calcium (Fraxiparin, 2850 IU anti-Xa) plus intra- and postoperative compression stockings until discharge in a cohort of 1954 consecutive patients who underwent spine surgery. Major postoperative hemorrhage was defined as a hemorrhage associated with a mass effect on postoperative spinal magnetic resonance imaging or neurologic deterioration, as well as a large-wound hematoma with intractable pain. Major postoperative hemorrhage occurred in 0.7% (13 of 1954) of spinal procedures, and 0.4% (8 of 1954) of major postoperative epidural hematomas developed after administration of nadroparin. Hematomas were surgically evacuated immediately after diagnosis. Six of the patients with postoperative hematomas developed a progressive neurologic deficit, which resulted in a hemorrhage-related residual neurologic impairment in 0.2% (3 of 1954) patients.
The risk of adverse bleeding events from antiplatelet agents was evaluated in 1 prospective cohort study that examined bleeding risks associated with Ketorolac.30 Forty-four consecutive patients undergoing lumbar microdiscectomy were given a single 30-mg intravenous dose of Ketorolac immediately before wound closure and were prospectively observed until discharge, whereas 45 patients who did not receive Ketorolac during lumbar microdiscectomy were evaluated retrospectively. There were no incidences of postoperative incisional bleeding complications or bleeding from the wound site. Platelet counts remained normal after surgery, and no abnormal laboratory values were noted.
Question 3. Is There a Safe Perioperative Window of Nonanticoagulation for These High-Risk Patients?
We found no studies that attempted to define a safe perioperative window of nonanticoagulation in spine surgery patients, nor did we identify any study that assessed this safe perioperative window in general surgery.
The overall strength of evidence with respect to incidence of thromboembolic events after spine surgery is “very low” to “low,” that is, any estimate of the effect reported for the various spine conditions is uncertain and further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. The overall strength of evidence for the incidence of significant hemorrhage secondary to anticoagulation use is also “very low,” that is, any estimate of effect is very uncertain. Finally, we found no evidence to support any preventive measures with respect to a safe perioperative window of nonanticoagulation for high-risk spinal surgery patients (Table 3).
This systematic review demonstrated that the risk of DVT in elective spine surgery without chemical prophylaxis was 1% to 2% and up to 18% in the trauma population. The risk of fatal PE in elective surgery is extremely low (no case identified) except in the trauma patients. We could not identify significant risk factors for thromboembolic diseases except for trauma in spine surgery patients.
Postoperative bleeding with possibility of epidural hematoma and neurologic complications occur in 1% to 3.5% of cases of patients receiving heparin but did not occur in single studies of patients receiving aspirin, Ketorolac or Warfarin. If heparin is to be used, careful monitoring of the wound and neurologic examination should be performed. Postoperative hemorrhage from wounds also occurred in 1% to 3% of cases treated with chemical prophylaxis, but the significance seemed minor. The data reviewed did not provide adequate information of the timing of administration of chemical prophylaxis and its effect on patient safety; therefore, we could not identify any evidence regarding the safe timing of chemical anticoagulation.
We stratified risk of bleeding complications in patients receiving anticoagulation therapy by the agent administered. However, the small number of studies available limits the conclusions with respect to which agents provide the least risk. Additional studies added to those collected here will provide a more robust estimate in determining whether one agent is safer than another.
This systematic review will likely under represent the true incidence of VTE because the sensitivity of diagnostic tests are <100%, and episodes of VTE may occur after such testing has been performed. Further, the many confounding variables present in these patients may obscure important factors associated with VTE risk and the evaluation of the safety of prophylaxis.
Previous Clinical Guidelines
The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition) provides recommendations for prevention of VTE in elective spinal surgery.1 For patients with no additional risk factors, the recommendations are against the routine use of any thromboprophylaxis modality beyond early and persistent mobilization. For patients with additional risk factors such as advanced age, malignancy, presence of neurologic deficit, previous thromboembolism, or an anterior surgical approach, any of the following prophylaxis options are recommended: (1) postoperative low-dose unfractionated heparin (LDUH) alone, (2) postoperative LMWH alone, or (3) perioperative intermittent pneumatic compression (IPC) alone. Other considerations include perioperative graduated compression stockings (GCS) alone or perioperative IPC combined with GCS. In patients with multiple risk factors for VTE, it is recommended to combine LDUH or LMWH with GCS or IPC.
Similarly, the North American Spine Society Evidence-Based Clinical Guideline on Antithrombotic Therapies in Spine Surgery has provided evidence-based recommendations regarding antithrombotic therapies in spine surgery.32 Mechanical compression devices in the lower extremities are suggested to be initiated in elective spinal surgery just before surgery, and continuing until the patient is fully ambulatory. Chemoprophylaxis may not be warranted in most common elective spine surgeries performed through a posterior approach. LMWH or LDUH may be used after surgery after elective combined anterior-posterior spine surgery or in patients identified as having a high risk for VTE, such as multiple trauma, malignancy, or hypercoagulable state.
Based on the low risks of fatal PE in elective surgery, it was the opinion of experts that chemical prophylaxis to prevent thromboembolic disease is not routinely indicated. The use of thromboembolic stockings and mechanical compression devices is recommended on a case-by-case basis. Chemical prophylaxis should be considered in patients with significant neurologic dysfunction or who require prolonged bed rest, although this scenario was not evaluated in this study. If heparin is used, then careful observation of the wound and neurologic functions should be performed (Figure 3). Chemical prophylaxis should be considered in spinal trauma patients and those with spinal cord injuries.
- In elective spine surgery, the incidence of DVT and nonfatal pulmonary embolism without chemical prophylaxis is 1% to 2%. Fatal pulmonary embolism is extremely rare.
- Trauma patients are at increased risk, and chemical prophylaxis should be considered.
- The safe timing of the administration of anticoagulation agents is unknown.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.spinejournal.com).
The authors thank Ms. Nancy Holmes, RN, for her administrative assistance and Ms. Erika Ecker, BS, for her assistance in searching the literature, abstracting data, and proofing.
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