### Evidence Report/Technology Assessment: Number 22

# Prevention of Venous Thromboembolism After Injury

## Summary

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality(AHRQ) is developing scientific information for other agencies and organizations on which to baseclinical guidelines, performance measures, and other quality improvement tools. Contractorinstitutions review all relevant scientific literature on assigned clinical care topics and produceevidence reports and technology assessments, conduct research on methodologies and theeffectiveness of their implementation, and participate in technical assistance activities. 

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report

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## Overview

Venous thromboembolism (VT) is a major national health problem, claiming 50,000 lives and resulting in 300,000 to 600,000 hospitalizations annually in the United States. VT presents in two forms:

- Deep venous thrombosis (DVT). 
- Pulmonary embolism (PE). 

Injured patients are at high risk for VT because of changes in coagulation and thrombolysis mechanisms that are induced by trauma. 

Methods for preventing VT include, among others:

- Sequential compression devices (SCDs). 
- Low-dose heparin (LDH). 
-  Low-molecular-weight heparin (LMWH). 
-  Vena caval filters (VCFs). 
-  Combinations of these. 

All of these methods are associated with contraindications and morbidity. Therefore, selecting the appropriate method for the appropriate trauma patient is important. The difficulty of selecting the appropriate prophylaxis is in part a result of the inconclusiveness of the relevant trauma literature. This allows wide variability among physician practices and prevents consistency in quality of care. 

With this report, we evaluate and meta-analyze the existing data in the literature to produce scientific answers in controversial areas related to this topic. We also identify research gaps in areas in which the scientific evidence is absent or minimal. Also, we hope to assist interested organizations in producing relevant guidelines and directing future research.

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## Reporting the Evidence

A panel of 17 technical experts, consisting of national authorities in the field and representing the academic, private, and managed care sectors, was formed to assist in the design and execution of the project. Important questions on the topic were distributed to the experts, who ranked them in order of importance. After two conference calls, several refined key questions were developed: 

- 	What is the best method of prevention of VT after injury? 
- 	Which groups of trauma patients are at high risk of developing VT? 
- 	What is the best method of screening for VT in trauma patients? 
- 	What is the role of VCF in preventing PE after injury? 

The panel decided to use data restricted to trauma patients only and avoid extrapolation of conclusions from nontrauma patients to the trauma population. Defining "the trauma patient" was difficult. The panel decided to exclude elderly patients with injuries following low-energy trauma (e.g., hip fractures after ground-level falls) from consideration. We subsequently developed causal pathways for each key question. We believed that it was important to report on the rates of DVT and PE from combined literature data because these rates varied widely among studies.

We summarized the existing evidence on all trauma patients included in the available literature as well as that on individual trauma patient groups (i.e., orthopedic trauma, neurosurgical trauma, minor trauma) when data were available. We evaluated the quality of studies included in our analysis using previously published methods of determining quality scores. We entered all data in a computerized database specifically designed for this project. 

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## Methodology

We searched three literature databases:

- MEDLINE (1966-January 31, 1999).
- 	 EMBASE (1980-January 31, 1999).
- 	The Cochrane Controlled Trials Register (1980-January 1999).

After a broad initial search, we performed multiple literature searches tailored to each question. Finally, we identified a total of 4,093 titles, which were screened according to specific inclusion and exclusion criteria by three independent medical reviewers. The third reviewer assisted in case of disagreements.

After screening, 2,437 titles were accepted for abstract review. The three reviewers screened all abstracts against specific criteria; 227 of these were accepted for complete review. Of 225 articles retrieved, 73 were accepted for meta-analysis.

We designed forms to extract relevant data on study design and quality, methods used, risk factors, and outcomes. Two reviewers extracted data, which were cross-examined by the third. Discrepancies were resolved in meetings among all three reviewers. A random-effects model was used for all pooled results.

We first evaluated the reported incidence of DVT and PE in trauma patients. We extracted these rates from all studies as well as from studies grouped together by study design (randomized, nonrandomized comparative cohorts, single cohort), method of VT diagnosis (routine screening or based on clinical suspicion), use of VT prophylaxis (yes or no), and type of trauma patients (i.e., all trauma, orthopedic trauma, neurosurgical trauma, minor trauma).

We addressed the question of the best method of VT prophylaxis in three ways:

- 	We examined the incidence of DVT and PE after combining groups of patients from different randomized trials who received LDH or LMWH or mechanical prophylaxis (MP) or no prophylaxis. 
- 	We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the same methods of prophylaxis. 
- 	We performed a meta-analysis of RCTs and non-RCTs, evaluating the same methods of prophylaxis. 

This last meta-analysis, although methodologically weak, was performed because the number of RCTs available for the first meta-analysis was limited.

We addressed the question of risk factors for developing VT by performing a meta-analysis on studies (RCT and non-RCT) that used risk factors as either dichotomous variables (e.g., age greater or less than 55) or continuous variables (e.g., age, without specifying a particular age cutoff point). We evaluated six dichotomous risk factors (gender, head injury, long-bone fracture, pelvic fracture, spinal fracture, and spinal-cord injury) and three continuous risk factors (age, Injury Severity Score [ISS], and units of blood transfused).

We were unable to address the question about methods of screening for VT using the current literature data. Only three studies addressed this issue in trauma patients, and each compared different methods of screening. The data could not be combined for analysis.

We addressed the question about VCF by combining studies that included patients treated with VCF and patients without VCF and estimating the rates of PE in the two groups. None of these studies was an RCT. Other outcome parameters relevant to VCF placement, such as related complications, long-term outcome, or appropriate population to be treated with this modality, could not be extracted from the limited data available.

We also performed supplemental analyses on the two most frequent complications related to prophylactic heparin administration—bleeding and thrombocytopenia—as well as on the incidence of fatal PE and the length of hospital stay in patients who develop VT. Finally, we developed a cost-effectiveness model.

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## Findings

The main findings from this evidence report include the following:

- 	The reported incidence of DVT and PE varies widely among different studies depending on study design, type of trauma patients included, and methods of screening and prophylaxis. The pooled rates of DVT and PE across all studies are 11.8 percent (95 percent confidence interval [CI]: 0.104, 0.131) and 1.5 percent (95 percent CI: 0.011, 0.018), respectively. 
- 	Only a few RCTs address methods of VT prophylaxis in trauma patients. Most of these studies use different methods. Combining the limited data from studies using the same methods produces small sample sizes. 
- 	LDH is not statistically superior to no prophylaxis in preventing VT after injury (odds ratio [OR]: 0.965, 95 percent CI: 0.353, 2.636). This conclusion is based on a meta-analysis of four RCTs with a total of 219 patients. 
- 	MP is not statistically superior to no prophylaxis in preventing VT after injury (OR: 0.769, 95 percent CI: 0.265, 2.236). This conclusion is based on a meta-analysis of three RCTs with a total of 234 patients. 
- 	The addition of non-RCTs to the meta-analyses of studies examining DVT rates in trauma patients receiving LDH vs. no prophylaxis or MP vs. no prophylaxis does not change these conclusions. 
- 	Comparison of LMWH vs. LDH shows no statistically significant difference between the two methods in preventing PE (OR: 3.010, 95 percent CI: 0.585, 15.485). This conclusion is based on a meta-analysis of three studies reporting on the incidence of PE (two RCTs and one non-RCT, total number of patients: 355). Although the difference in PE rates is not statistically significant, the limits of the 95 percent CI for this result are very wide. 
- 	Three RCTs (one of them with the highest possible quality score) showed separately statistical superiority of LMWH against LDH or SCD in preventing DVT. The reported DVT rates vary widely among these studies (38 percent, 7 percent, and 2 percent). Because the method of prophylaxis used to compare against LMWH was not the same, a meta-analysis was not done. 
- 	Comparison of LDH vs. MP after meta-analysis of seven studies (four RCTs and three non-RCTs, total number of patients: 620) shows no statistically significant difference between the two methods in preventing DVT (OR: 1.161, 95 percent CI: 0.495, 2.723). 
- 	Spinal fractures and spinal-cord injury are risk factors for DVT. Other frequently reported risk factors, such as head injury, pelvic fractures, or long-bone fractures, were not shown in the meta-analysis to increase the risk for DVT. It is possible that the studies reporting on these factors included severely injured patients who were already at high risk regardless of the presence of the individual risk factor. 
- 	Trauma patients who develop DVT are older and have more severe injuries than patients who do not develop DVT. However, a specific age or ISS threshold could not be extracted from the available data. 
- 	The reported incidence of PE in patients who undergo VCF placement is 0.2 percent, which is lower than the incidence observed in concurrently managed patients without VCF (1.5 percent) and historical controls without VCF (5.8 percent). The observational design of these studies does not allow firm conclusions to be drawn. 
- 	LDH or LMWH administration for VT prophylaxis produces a low and similar incidence of adverse events (on average, 3 percent for bleeding and 1 percent for thrombocytopenia). These low rates may occur because patients at high risk for bleeding were not given heparin. 
- 	Fatal PE has been reported in one-third of trauma patients who develop PE, based on data from 16 studies that reported on both rates (PE, and fatal PE). 
- 	The length of hospital stay in patients who develop DVT is significantly longer (by 15 days) than for patients without DVT. Although a cause-effect relationship between DVT and length of hospital stay cannot be established, DVT is associated with increased costs and use of health care resources. 
- 	There are significant gaps in the literature regarding the prevention of VT after trauma.

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## Future Research

Future research should be directed to two areas:

- Identifying the appropriate groups of trauma patients in need of VT prophylaxis. 
- 	Evaluating different methods of prophylaxis with regard to their safety and efficacy in trauma patients.

Although evaluating different methods of screening for DVT would be useful, we do not feel that this should be a priority for future research. Duplex ultrasonography is the most convenient, noninvasive, and inexpensive method of screening severely injured patients. Even if other methods of screening prove to be more sensitive, associated technical and logistical difficulties make them impractical. 

To address these two areas, we propose a large multicenter trial. This trial should have a randomized controlled design, compare the most commonly used methods of prophylaxis (LDH, LMWH, SCD), identify DVT by routine screening, and evaluate multiple risk factors. A no-prophylaxis group should be included, following the results of this evidence report.

Equally important future research should be directed towards evaluating the role of VCF in trauma patients. This question could be incorporated in our proposed multicenter trial or become the sole objective of a separate randomized trial. Both designs should have a predetermined protocol for diagnosing PE:

- An aggressive autopsy policy to identify the cause-effect relationship of PE to death. 
- Careful, long-term followup to detect VCF-related complications.

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## Availability of Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Southern California Evidence-based Practice Center/RAND under contract  No. 290-97-0001. Print copies of this report are available free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment  No. 22, *Prevention of Venous Thromboembolism After Injury* (AHRQ Publication  No. 00-E027). 

The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.

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*AHRQ Publication Number 00-E026Current as of August 2000*

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**Internet Citation:**

*Prevention of Venous Thromboembolism After Injury*. Summary, Evidence Report/Technology Assessment: Number 22, August 2000. Agency for Healthcare Researchand Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/vtsumm.htm

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