Venous thromboembolism chemoprophylaxis is not supported following elective spine surgery: a systematic review and meta-analysis of randomized controlled trials

Introduction

Postoperative venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a rare but significant postoperative complication following spinal surgery. The prevalence of VTE in patients following spine surgery ranges widely from 0.3% to 31% in previous studies, largely being influenced by surgical and patient-specific risk factors (1). To prevent the development of VTE in the postoperative period, surgeons may employ either mechanical prophylaxis, chemoprophylaxis, or both (2). Mechanical prophylaxis includes the use of compression stockings such as thrombo-embolic deterrent (TED) hose or sequential compression devices (SCDs). These devices reduce venous stasis via compression of the superficial venous systems, increasing venous velocity, and stimulating endogenous fibrinolysis (3). Common VTE chemoprophylaxis utilized by spine surgeons include unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) (4). These anticoagulant agents inhibit blood clotting by reversibly binding to antithrombin III (ATIII), which greatly accelerates the rate at which ATIII inactivates coagulation enzymes thrombin (factor IIa) and factor Xa (5).

While VTE chemoprophylaxis has been extensively studied in other surgical fields, there is a lack of evidence regarding its utility in spine surgery (6). This is suboptimal as degenerative spine disease is becoming increasingly prevalent worldwide, and more patients are undergoing surgical interventions as definitive treatment. Multiple factors contribute to the incidence of VTE after spine surgery, including extent of surgery (i.e., number of vertebral levels), type of surgery (i.e., fusion vs. non-fusion procedures), patient-specific risk factors (age, sex, comorbidities), and traumatic or oncologic operative indications (7). Spine surgeons must consider the potential risks associated with anticoagulants, such as bleeding and postoperative epidural hematoma.

Considering the unique challenges and risks associated with anticoagulation in this patient population, it is essential to gather high-quality evidence in order to assess the safety and effectiveness of VTE chemoprophylaxis regimens. Prior studies are limited in either scope or methodology (8,9). This systematic review and meta-analysis aims to examine existing research from randomized trials that compare VTE chemoprophylaxis vs. no chemoprophylaxis after elective spine surgery. The objective is to inform postoperative decision-making that may enhance outcomes at both the patient and health-system populations. We present this article in accordance with the PRISMA reporting checklist (10) (available at https://jss.amegroups.com/article/view/10.21037/jss-24-162/rc).

Methods

The review methods align with guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions (11).

Identification of studies

A thorough literature review was performed across several electronic databases, including PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials, covering the period from inception to May 8^th, 2023. The details of our search strategy can be found in Appendix 1.

Assessment of eligibility

The following criteria were used for study inclusion: (I) adult patients greater than 18 years of age who underwent elective spine surgery for degenerative changes or deformity; (II) perioperative use of any form of VTE prophylaxis (chemoprophylaxis or mechanical prophylaxis); (III) reporting specific outcomes of interest (occurrence of postoperative VTE, bleeding, and epidural hematomas); and (IV) a randomized controlled trial (RCT) design. We excluded studies performed in patients with traumatic or oncologic spinal conditions, non-human subjects, and the pediatric population. Two reviewers independently screened titles and abstracts using an electronic form and excluded irrelevant articles. The full text of the remaining articles (those considered relevant or uncertain) was then reviewed by two authors, who independently assessed whether they met the inclusion criteria for the meta-analysis. A senior author was available to settle disagreements. Non-English articles were read/translated by one of the co-authors.

Data extraction and risk of bias assessment

Study quality was graded by two independent reviewers using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) (12). A senior author settled disagreements. Efforts were made to contact study authors to retrieve any omitted information. Data were extracted by two authors independently, covering study objectives, demographics, and baseline characteristics, as well as surgical indications. The primary outcome measures that were extracted included VTE incidence, significant bleeding, and epidural hematoma. Significant bleeding was defined as bleeding that resulted in death, required reoperation, or necessitated greater than two postoperative transfusions.

Study definitions

For the purposes of this study, the chemoprophylaxis cohort involved patients from every included RCT (including data that could not be used in traditional pair-wise meta-analysis) who received coumadin, aspirin, LMWH, heparin-dihydroergotamine (HDHE), dihydroergotamine (DHE), rivaroxaban, and/or parnaparin in the perioperative period. The control cohort involved patients from every included RCT who received interventions such as placebo, compression stockings, and/or SCDs without accompanying chemoprophylaxis. In contrast, the chemoprophylaxis subgroup refers to patients included in traditional pair-wise meta-analysis who received HDHE, LMWH, or coumadin whereas the control subgroup refers to patients included in traditional pair-wise meta-analysis who received interventions such as placebo or compression stockings. All complications examined in this study used the original terms supplied by the authors of the included RCTs, including “significant” and “severe” bleeding.

Overall evidence assessment

This study did not utilize funnel plots for reporting bias assessment as Egger’s test for funnel plot asymmetry is unreliable with the small sample size present in this study. This study utilized the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence for each individual meta-analysis with possible certainty recommendations of high, moderate, low, or very low (13).

Statistical analysis

The Statistical Package for the Social Sciences (SPSS) software package version 29.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis of this study. A random effects dichotomous model was used for meta-analysis with risk ratio (RR) with 95% confidence intervals (CIs) as used elsewhere in the literature for similar studies with multiple different types of pharmacologic prophylaxis, patient populations, and spinal surgeries. Cases of zero were adjusted to 0.5, as used elsewhere in the literature, to allow for more comprehensive meta-analysis. Forest plots were generated to visually depict the relationships present between studies. Descriptive statistics were used for demographic information as needed. Significance levels for this study were set at P=0.05. Heterogeneity was defined as low if I²≤0.50.

Results

Search results

Our search identified 2,666 articles across all databases. After excluding 436 duplicates, a total of 2,230 titles and abstracts were screened. Fifteen full-text articles were assessed for inclusion eligibility, and of these, eight studies were ultimately deemed eligible for final inclusion (Figure 1).

Figure 1 PRISMA diagram of article selection.

Study characteristics, patient demographics, and extracted outcomes

A total of eight RCTs met final inclusion criteria for this systematic review and meta-analysis (14-21). Baseline characteristics, patient demographics, case inclusion/exclusion criteria of included studies are presented in Tables 1,2. Total included patients (n=1,509) had a mean age of 52.36±9.83 years. One study reported an average follow-up of 8 months, while two other studies reported an average follow-up of greater than 1 year. The other five included studies did not report on average follow-up. Patients (n=1,151) who received any form of VTE chemoprophylaxis (coumadin, aspirin, LMWH, HDHE, DHE, rivaroxaban, or parnaparin) following spine surgery in the chemoprophylaxis group had a mean age of 54.54±7.44 years. In contrast, patients (n=358) who did not receive chemoprophylaxis in the control cohort after spine surgery had a mean age of 49.40±11.75 years. Our analysis found that 1,207 patients (79.99%) in the included meta-analysis underwent lumbar surgery while 54 patients (3.58%) underwent either cervical or thoracic surgery. The remaining patients (n=248, 16.43%) underwent spine surgery in an unspecified region, which was not clearly documented. Table 3 displays the extracted data from included studies stratified by treatment group. Reported outcomes include rates of combined VTE, DVT, PE, significant bleeding, severe bleeding, and epidural hematoma. In six out of the eight included studies, there was no differences in patient-specific risks for hypercoagulability or comorbidities between treatment groups. The remaining two studies did not assess these characteristics.

Risk of bias

The risk-of-bias evaluations between reviewers were regarded as “moderate”, primarily due to different appraisals of expertise. These disagreements were easily settled by input from the senior author. The risk-of-bias assessment can be found in Figure 2.

Figure 2 Risk of bias assessment.

Risk for VTE risk for chemoprophylaxis vs. control

No significant difference was found in the incidence of VTE between the VTE chemoprophylaxis subgroup (n=108; 2 cases; 1.9% incidence) and the control subgroup (n=109; 3 cases; 2.8% incidence) via meta-analysis of four RCTs (RR: 1.01; 95% CI: 0.97, 1.05; P=0.68; Figure 3). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all RCTs, a total of 33 (2.45% incidence) cases of VTE occurred in the entire cohort (n=1,345, 89.13% reported). Twenty-eight cases (2.62% incidence) occurred in the chemoprophylaxis cohort (n=1,069, 92.88% reported) and 5 cases (1.81% incidence) occurred in the control cohort (n=276, 77.09% reported) with similar rates between cohorts (1.81% vs. 2.62%).

Figure 3 Forest plot for total VTE between chemoprophylaxis and control subgroups. CON, control; CP, chemoprophylaxis; RR, risk ratio; VTE, venous thromboembolism.

Risk of DVT risk for chemoprophylaxis vs. control

No significant difference was found in the incidence of DVT between the VTE chemoprophylaxis subgroup (n=190; 1 case; 0.5% incidence) and the control subgroup (n=191; 7 cases; 3.7% incidence) via meta-analysis of four RCTs (RR: 1.03; 95% CI: 0.99, 1.06; P=0.11; Figure 4). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all RCTs, a total of 32 cases (2.12% incidence) of DVT occurred in the entire cohort (n=1,509, 100% reported) Twenty-four cases (2.09% incidence) occurred in the chemoprophylaxis cohort (n=1,151; 100% reported) and 8 cases (2.23% incidence) occurred in the control cohort (n=358; 100% reported) with nearly identical rates of DVT between cohorts (2.09% vs. 2.23%).

Figure 4 Forest plot for risk of DVT between chemoprophylaxis and control subgroups. CON, control; CP, chemoprophylaxis; DVT, deep vein thrombosis; RR, risk ratio.

Risk of severe bleeding for chemoprophylaxis vs. control

No significant difference in the incidence of severe bleeding was found between patients in the VTE chemoprophylaxis subgroup (n=108; 1 case; 0.9% incidence) and patients in the control subgroup (n=109; 5 cases; 4.6% incidence) via meta-analysis of three RCTs (RR: 1.01; 95% CI: 0.97, 1.05; P=0.59; Figure 5). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all the RCTs, a total of 11 cases (1.01% incidence) of severe bleeding occurred in the entire cohort (n=1,094, 72.50% reported). Seven cases (0.74% incidence) of severe bleeding occurred in the chemoprophylaxis cohort (n=952, 82.71% reported) and 4 cases (2.82% incidence) of severe bleeding occurred in the control cohort (n=142, 39.66% reported) with similar rates of severe bleeding between cohorts (0.74% vs. 2.82%).

Figure 5 Forest plot for risk of severe bleeding between chemoprophylaxis and control subgroups. CON, control; CP, chemoprophylaxis; RR, risk ratio.

Risk of significant bleeding for chemoprophylaxis vs. control

There was no statistically significant difference in risk of significant bleeding between patients in the chemoprophylaxis subgroup (n=108; 6 cases; 5.6% incidence) as compared to patients in the control subgroup (n=109; 8 cases; 7.3% incidence) via meta-analysis of three RCTs (RR: 1.01; 95% CI: 0.97, 1.04; P=0.75; Figure 6). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all RCTs, a total of 65 cases (5.94%) of significant bleeding occurred in the entire cohort (n=1,094, 72.50% reported). Fifty-five cases (5.77%) in the chemoprophylaxis cohort (n=952, 82.71% reported) and 10 cases (7.04%) in the control cohort (n=142, 39.66% reported) with similar rates of significant bleeding between cohorts (5.77% vs. 7.04%).

Figure 6 Forest plot for RR of significant bleeding between chemoprophylaxis and control subgroups. RR, risk ratio; CP, chemoprophylaxis; CON, control.

Risk of PE for chemoprophylaxis vs. control

No significant difference was found in the incidence of PE between the VTE chemoprophylaxis subgroup (n=108; 1 case; 0.9% incidence) and the control subgroup (n=109; 0 cases; 0.0% incidence) via meta-analysis of three RCTs (RR: 1.00; 95% CI: 0.96, 1.03; P=0.81; Figure 7). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all the RCTs, a total of five cases (0.37% incidence) of PE occurred in the entire cohort (n=1,345; 89.13% reported). Four cases (0.37% incidence) of PE occurred in the chemoprophylaxis cohort (n=1,069; 92.88% reported) and one case (0.36% incidence) of PE occurred in the control cohort (n=276, 77.09% reported) with identical rates of PE between cohorts (0.37% vs. 0.36%).

Figure 7 Forest plot for RR of PE between chemoprophylaxis and control subgroups. CON, control; CP, chemoprophylaxis; PE, pulmonary embolism; RR, risk ratio.

Risk of epidural hematoma for chemoprophylaxis vs. control

There was no statistically significant difference in risk of epidural hematoma between patients in the chemoprophylaxis subgroup (n=108; 0 cases; 0.0% incidence) as compared to patients in the control subgroup (n=109; 0 cases; 0.0% incidence) after meta-analysis of three RCTs (RR: 1.00; 95% CI: 0.97, 1.03; P>0.99; Figure 8). Heterogeneity was low for this outcome (I²=0.0%) with “moderate certainty”. For absolute pooled data from all the RCTs, a total of one case (0.1% incidence) of epidural hematoma occurred in the entire cohort (n=1,094; 72.5% reported). One case (0.1% incidence) of epidural hematoma occurred in the chemoprophylaxis cohort (n=952; 82.7% reported) and zero cases (0.0% incidence) of epidural hematoma occurred in the control cohort (n=142, 39.7% reported) with identical rates of epidural hematoma between cohorts (0.1% vs. 0.0%).

Figure 8 Forest plot for RR of epidural hematoma between chemoprophylaxis and control subgroups. RR, risk ratio; CP, chemoprophylaxis; CON, control.

Discussion

This meta-analysis is the first to synthesize data including only RCTs comparing chemoprophylaxis vs. no chemoprophylaxis following spine surgery. The results show that with moderate certainty, there was no significant difference between the chemoprophylaxis subgroup and the control subgroup in the incidence of VTE (RR: 1.01; 95% CI: 0.97, 1.05; P=0.68) or DVT (RR: 1.03; 95% CI: 0.99, 1.06; P=0.11). Furthermore, no significant difference was found between groups in the incidence of severe bleeding (RR: 1.01; 95% CI: 0.97, 1.05; P=0.59), significant bleeding (RR: 1.01; 95% CI: 0.97, 1.04; P=0.75), PE (RR: 1.00; 95% CI: 0.96, 1.03; P=0.81), or epidural hematoma (RR: 1.00; 95% CI: 0.97, 1.03; P>0.99). There was only one reported symptomatic epidural hematoma in the Du et al. 2015 study (14). Overall, our results suggest that the routine use of chemoprophylaxis following spine surgery may not reduce rates of VTE or result in a higher risk of bleeding or clotting complications, although caution should be used as these results may be underpowered.

When looking at the existing literature on DVT and PE rates in spine surgery, a study involving 578,000 patients who underwent lumbar spine surgery from 2002 to 2009 found a DVT and PE incidence of 0.24% and 0.1% respectively following lumbar decompression. These rates increased slightly following lumbar fusion surgery to 0.43% and 0.26% (22).

Of course, not all spine surgery carries the same postoperative VTE risk. Polytrauma patients with spine fractures or spinal cord injury and patients with spinal tumors carry an elevated VTE risk postoperatively (23). On the same note, patient-specific factors such as age, medical comorbidities, baseline activity level, prior DVT/PE, and medications are all possible contributing factors in the development of VTE. Arthrodesis historically played a larger role as a risk factor for development of VTE, however, with modern interbody implants combined with minimally invasive techniques, fusion is no longer as much of a factor when considering a patient’s postoperative VTE risk when compared to more traditional techniques (24).

In considering the routine use of chemoprophylaxis after spine surgery, surgeons must ultimately weigh the pros and cons of the consequences of DVT/PE vs. epidural hematoma. A previous meta-analysis looking at 4,383 patients after elective spine surgery found a DVT rate of 1.90%, a PE rate of 0.06%, and only one patient in the cohort had a fatal PE. In the same cohort, eight patients developed an epidural hematoma which required surgical evacuation, and three went on to develop permanent neurological deficits (25). Many DVTs can be safely treated with LMWH and/or oral anticoagulants for 3 months depending on patient risk factors (26). Symptomatic epidural hematoma necessitates a repeat surgical procedure for hematoma evacuation and hemostasis, subjecting patients to additional perioperative risks and healthcare costs. Readmissions for spine irrigation and debridement reoperations have been demonstrated to incur hospital costs of approximately $13,000 (27).

When considering the appropriate method of VTE prophylaxis in the postoperative period, some societal guidelines are published to help guide decision making. The North American Spine Society (NASS) currently recommends routine mechanical prophylaxis starting before or at the start of surgery until patients are mobilizing postoperatively. With regards to VTE chemoprophylaxis, the NASS guidelines note that posterior elective spinal surgeries have a very low risk of VTE, and therefore chemoprophylaxis may not be necessary in these situations. The results of this study corroborate the recommendations of those guidelines. The guidelines recommend that when VTE chemoprophylaxis is used, close monitoring of patients’ neurological status should be performed (28).

The American College of Chest Physicians 2012 guidelines recommend mechanical prophylaxis or LMWH for patients undergoing routine elective spinal surgery. For patients deemed to be higher risk, such as those with malignant disease or patients undergoing combined anterior-posterior surgery, pharmacologic VTE prophylaxis is recommended once hemostasis is achieved. In patients with spinal tumors or trauma requiring surgery, the guidelines recommend VTE pharmacotherapy in addition to mechanical prophylaxis (29). Ultimately, these guidelines serve as a useful reference to help guide educated decision-making in the postoperative period. However, we posit that surgeons should tailor their approach based on patient-specific risk factors and surgical procedure.

There are limitations to our present study. As with any meta-analysis, our criteria significantly limited the number of studies that qualified for inclusion, suggesting that our analyses may be underpowered. Given the limited evidence available on this topic, data were pooled into over-arching groups. This inherently increases the overall heterogeneity as the comparison arms involved chemoprophylaxis and mechanical prophylaxis regimens with substantial variability. In addition, inherently different surgeries, i.e., decompression alone vs. decompression and fusion, were grouped together, and subgroup analysis could not be completed due to lack of available data. Furthermore, the patients in this study had varying indications for spine surgery (such as degenerative disease vs. spinal deformity), for which disposition differed as well. For example, lumbar microdiscectomy and 1–3 level surgery for degenerative disease are often outpatient surgeries while thoracolumbar deformity correction with or without three-column osteotomies is almost always an inpatient stay. These variables could not be analyzed due to differences in study design and power in the included studies. Surgeons should also be aware that different comorbidities, such as chronic kidney or liver disease, can alter the risk of postoperative complications and this study did not comment on how patient-specific risk factors affect risk of VTE. There was also variability in outcome measures between included studies, such as how postoperative VTE was screened, i.e., obtain ultrasound prior to discharge or obtain ultrasound only if symptomatic. Furthermore, this study used terms original to each RCT, such as “severe” or “significant bleeding”, which may lead to additional heterogeneity. Further research validating VTE risk in subgroups such as minimally invasive vs. open approach, decompression vs. fusion, hospital length of stay, and other criteria in patients undergoing elective spine surgery is needed.

Conclusions

This systematic review and meta-analysis of RCTs reports that the use of chemoprophylaxis following elective spine surgery does not significantly affect the risks of developing VTE, DVT, PE, severe bleeding, significant bleeding, or epidural hematoma. In line with current guidelines, the use of routine VTE chemoprophylaxis following spine surgery should be carefully assessed for each patient after considering both surgical and patient-specific risk factors. As these findings may be underpowered due to the rarity of these conditions, more high-quality research is needed with cautious consideration of the results of this study in the interim.

Acknowledgments

A version of this article was presented in abstract format at the North American Spine Society (NASS) 2024 annual meeting.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-24-162/rc

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-24-162/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-24-162/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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