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10.1245/s10434-006-9183-9
Annals of Surgical Oncology 14:929-936 (2007)
© 2007 Society of Surgical Oncology
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Original Article

A Systematic Review of Deep Venous Thrombosis Prophylaxis in Cancer Patients: Implications for Improving Quality

Michael J. Leonardi, MD1,2, Marcia L. McGory, MD1,2 and Clifford Y. Ko, MD, MSHS1,2,3

1 UCLA Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
2 UCLA Center for Surgical Outcomes and Quality, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
3 Department of Surgery, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

Correspondence: Address correspondence and reprint requests to: Michael J. Leonardi, Department of Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 72-215 CHS, Box 956904, Los Angeles, CA 90095-6904, USA; E-mail: mjleonardi{at}mednet.ucla.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Deep venous thrombosis (DVT) prophylaxis is particularly important for surgical oncologists given the high rate of DVT in patients with malignancy. Additionally, DVT prophylaxis may soon be implemented by some payers as a "pay for performance" quality measure. This is a systematic review of randomized controlled trial (RCT) evidence for DVT prophylaxis in cancer patients undergoing surgery. We examine overall rates of DVT, the efficacy of high versus low-dose heparin prophylaxis, and the rate of bleeding complications.

Methods: The Medline database was searched for English language RCTs using key words DVT, venous thromboembolism, prophylaxis, and general surgery. Inclusion criteria were RCTs evaluating surgical oncology patients.

Results: Fifty-five RCTs studied DVT prophylaxis in surgery (nonorthopedic) patients. Twenty-six RCTs evaluated 7,639 cancer patients. The overall DVT rate was 12.7% for pharmacologic prophylaxis and 35.2% for controls. High-dose low-molecular weight heparin (LMWH) was more effective than low dose, lowering the DVT rate from 14.5% to 7.9% (P < 0.01). Heparin decreased the rate of proximal DVTs. Bleeding complications requiring discontinuation of prophylaxis occurred in 3% of the patients. There was no difference between LMWH and unfractionated heparin in efficacy, DVT location, or bleeding complications.

Conclusion: Using RCT data, this study demonstrates a greatly reduced DVT rate with pharmacologic prophylaxis in cancer patients, and higher doses appear more effective. Complication rates are low and should not prevent the use of prophylaxis in most patients. Finally, we found no difference between LMWH and unfractionated heparin in these RCTs. These results highlight the importance of routine pharmacologic prophylaxis in surgical patients with malignancy.

Key Words: DVT • Prophylaxis • Cancer • Surgery • Heparin • Review


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Deep venous thrombosis (DVT) causes significant morbidity and mortality in postsurgical patients. Of those afflicted with DVT, 23% develop a post-thrombotic syndrome within 2 years, characterized by chronic pain, swelling, and possibly skin ulceration. There is no significant association between occurrence of this syndrome and size and location of the thrombus. In addition, 25% of afflicted patients will suffer a DVT recurrence within 5 years. DVTs also cause significant mortality with pulmonary embolisms (PE). Fifty percent of patients with known DVTs will develop a PE and these kill an estimated 60,000 patients annually. Importantly, 70% of patients with PEs, had undiagnosed DVTs, meaning that failure to provide proper prophylaxis may lead to development of undiagnosed DVTs that cause PEs after hospital discharge.1

In general surgery, up to 40% of patients will develop a DVT without prophylaxis and the presence of malignant disease increases their risk at least twofold.2 Despite this high rate of DVT and these serious risks to patients, surgeons have performed poorly with respect to DVT prophylaxis. It has recently been shown that 25% of high-risk abdominal surgery patients receive no prophylaxis and 50% receive inadequate prophylaxis.3

With the current trend towards improving quality and outcomes in surgery using evidence-based guidelines, the focus on DVT prophylaxis is increasing. Programs such as the Surgical Care Improvement Project (SCIP) have arisen, which is a collaboration of agencies including the Centers for Medicare and Medicaid Services, the Centers for Disease Control and Prevention, the American College of Surgeons, and the Department of Veterans A3airs. The overarching SCIP goal is to decrease the postsurgical complications by 25% by 2010 using four target areas. Prevention of DVT is one of these areas.4 Additionally, as payers such as Medicare make Pay for Performance a reality, DVT prophylaxis will likely be an area of focus.

DVT prophylaxis has long been considered important in surgical oncology since malignancy is a known risk factor for development of DVT. Despite these high risks, providers have largely been left on their own to determine the proper prophylaxis for their patients. As quality improvement organizations focus on DVT prophylaxis in surgical patients, surgical oncologists will be faced with increasing pressure to create guidelines for appropriate prophylaxis in their own hospitals. Thus, the aims of the current study are to perform a systematic review of all randomized controlled trials (RCT) of DVT prophylaxis in surgical oncology patients to determine the following: (1) overall rate of DVT and how this is influenced by the detection method used; (2) efficacy of high- and low-dose heparin prophylaxis and how this affects DVT location (proximal vs. distal); and (3) rate of bleeding complications associated with pharmacologic prophylaxis.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Literature Search
MEDLINE (1966–2005) was searched for studies involving DVT prophylaxis in general surgery. Key words included were: DVT, venous thromboembolism, prophylaxis, and general surgery. Search results were limited to English language RCTs involving general surgery, urology, gynecology, and thoracic (excluding cardiac) surgery patients. A manual bibliographic survey of all identified articles was performed to identify additional studies. In addition, bibliographic surveys of previous meta-analyses and systematic reviews of DVT prophylaxis were performed.

Study Selection
For the articles identified in the literature search, inclusion criteria were RCTs of DVT prophylaxis including surgical oncology (general, colorectal, gynecologic, noncardiac thoracic, and urologic cancer) patients. Exclusion criteria were RCTs that did not include patients with malignancy or did not give DVT rates on malignancy patients.

Data Collection
Data was abstracted from each RCT and then independently reviewed by the authors. Disagreements were resolved by consensus. Data abstracted for all studies included name of first author, journal, year of publication, number of patients randomized, patient age, patient gender, presence of malignancy, type of surgery, intervention type and duration (including discontinuation rate), number of bleeding complications, number of DVTs, location of DVTs (distal vs. proximal), and method of DVT detection. Complications were pooled into minor (epistaxis, asymptomatic hematuria, injection site bruising, and wound hematoma) and major (reoperation due to bleeding, retroperitoneal bleed, gastrointestinal bleed, and intracranial bleed) groups. The rate of discontinuation of prophylaxis was also determined.

Analysis
The average age was calculated using a weighted average of the mean age from each RCT. When the average age was not provided for the malignancy subgroup within a study, the mean age of the entire sample was substituted. When the average age was not provided for any of the patients in a study, these patients were excluded from the weighted average age calculation. The percentage of males was calculated using the number of males as the numerator and the total number of patients as the denominator. Again, when a RCT did not provide gender information for the malignancy subgroup, the percentage of males from the overall sample was substituted, and if the study did not provide gender information on any patients then these patients were excluded from the gender calculation.

Patients were pooled from all studies into groups based on intervention received: low-molecular weight heparin-high dose (LMWH-H), low-molecular weight heparin-low dose (LMWH-L), low-dose unfractionated heparin-high dose (LDUH-H), low-dose unfractionated heparin-low dose (LDUH-L), a placebo group, and a combination pharmacologic–mechanical prophylaxis group. For LMWH, high dose was defined as greater than 3,400 units daily and for LDUH, high dose was defined as 5,000 units three times per day (low dose was defined as any lower amount). These definitions were consistent with previous reviews and guidelines.2,5

The overall rate of DVT was calculated for each of the following groups: all pharmacologic prophylaxis combined, each of the intervention groups, and each method of DVT detection. The overall DVT rate was calculated by pooling all potential patients as the denominator and those afflicted with DVT as the numerator. Comparisons of DVT rates by intervention were made using a standard t-test; a two-sided P < 0.05 was considered statistically significant. The rate of proximal DVTs was determined using the number of DVTs as the denominator and the number of DVTs in the popliteal vein and above as the numerator. Bleeding complications rates were determined using the number of patients as the denominator and the number of complications (e.g., minor or major) as the numerator. All analyses were performed using STATA version 9.1 (College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Information
Fifty-five RCTs studying DVT prophylaxis in general surgery patients (including general, colorectal, gynecologic, noncardiac thoracic surgery, and urologic cancers) were identified through the initial literature search. Twenty-six of the 55 RCTs were included in the current review, because they included patients with malignancy and performed a subgroup analysis of the rate of DVT in these patients. The remainder of the studies did not include malignancy patients (one study), did not provide the number of patients with malignancy (three studies), or did not provide the rate of DVT in these patients (29 studies). As such, our analysis on DVT prophylaxis included 7,639 surgical oncology patients. The publication date of these studies ranged from 1975 to 2002. All RCTs initiated prophylaxis preoperatively. Most studies gave the first dose 2 h preoperatively, while some gave the first dose the night prior to surgery. The duration of prophylaxis ranged from 4 to 10 days with a median of 7 days, except for one study that extended prophylaxis in one arm to 4 weeks. Most studies explicitly stated that they encouraged early ambulation and discontinued prophylaxis on full ambulatory status or discharge from the hospital.

Overall, the average of the 7,639 patients was 63.4 years and 49.4% were males, as shown in Table 1Go. The following types of operations were performed: 39% colorectal, 38% abdominal surgery not otherwise specified (NOS), 11% esophageal/gastrointestinal, 5% other, 3% gynecologic, and 1% each of urologic, biliary, pancreatic, and noncardiac thoracic.


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  		TABLE 1. Study information
 
DVT Rates by Detection Method
Twenty-four RCTs performed routine DVT testing with the fibrinogen uptake test (FUT), venography, or ultrasound on 5,933 patients as shown in Table 2Go.6–29 For those patients receiving no prophylaxis, the rate of DVT was 35.2%. For patients receiving LDUH or LMWH (low- or high dose) the rate of DVT was 12.7% and for those patients receiving a combination of heparin and mechanical prophylaxis the rate was 5%. A subgroup analysis of the RCTs based on the DVT detection method was performed. For the 17 RCTs using the FUT detection method in 4,005 patients, the DVT rate without prophylaxis was 36.7%.6–9,11,13–20,23,26,28,29 For those patients receiving LDUH or LMWH (low- or high dose) prophylaxis the DVT rate was 11.1% and for those receiving a combination of heparin and mechanical prophylaxis the DVT rate was 5%, based on FUT detection method. Venography detected a higher rate of DVT than FUT. For the five RCTs using the venography detection method in 1,857 patients, the DVT rate with LDUH or LMWH (low-or high dose) was 16.4%.12,21,24,25,27 Ultrasound detected a lower rate of DVT than FUT. For the two RCTs using the ultrasound detection method in 107 patients, the DVT rate for patients receiving no prophylaxis was 6.3% and for those receiving LDUH or LMWH (low- or high dose) it was 1.8%.10,22 Finally, the rate of DVT detection in patients receiving LDUH or LMWH (low- or high dose) was 0.2% when clinical exam was used.30,31


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  		TABLE 2. Deep venous thrombosis (DVT) rates
 
DVT Rates by Dose and Type of Heparin
A subgroup analysis was performed to determine the efficacy of the high- versus low dose LDUH and LMWH, as shown in Table 3Go. This was only possible for the 17 RCTs that used the FUT because this was the only group that contained all of the dosage subgroups. While there was no difference between LDUH and LMWH (P > 0.50), for both medications the higher dose groups had a lower DVT rate than the low dose groups. For LDUH, the low dose group had a DVT rate of 13.4% and this was decreased to 8.0% in the high dose group (P-value = 0.0132). For LMWH, the low dose group had a DVT rate of 14.5% and this was decreased to 7.9% in the high dose group (P-value < 0.0001).


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  		TABLE 3. Deep venous thrombosis (DVT) rates by dose and type of heparin prophylaxis
 
DVT by Location
DVT location was examined in nine RCTs including 284 patients.9,12,21–25,27,28 For patients receiving no prophylaxis, 41.4% of DVTs were in the proximal location. This rate was significantly lower at 12.7% in patients who received LDUH or LMWH (P = 0.0001). There was no difference in DVT location for patients receiving LDUH versus LMWH (P = 0.83).

Bleeding Complications Due to Heparin Prophylaxis
Minor complications were evaluated in seven RCTs with 2,114 patients and occurred in 10% of patients.12,18,20,23–25,31 Major complications were evaluated in seven RCTs with 2,083 patients and occurred in 1% of patients.12,20,23–25,27,31 The rate of discontinuation of heparin prophylaxis due to bleeding in the high dose groups was evaluated in four RCTs with 1,668 patients and occurred in 3% of patients.18,24,25,27 There were no RCTs comparing the low dose groups. There was no difference between the LDUH and LMWH groups for minor complications, major complications, or the discontinuation of prophylaxis (P > 0.50 for all).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This review of 26 RCTs included 7,639 patients and established the rate of DVT in surgical oncology patients without prophylaxis at 35.2%. It also demonstrated that heparin (LMWH and LDUH) decreased this rate to 12.7% and the combination of heparin and mechanical prophylaxis further decreased the rate to 5%. We have also shown that the method of DVT detection has significant effect on the reported DVT rate with venography and FUT having higher rates than ultrasound. Studies that rely on clinical exam to perform testing have the lowest reported DVT rates. Our analysis showed no difference in efficacy between LMWH and LDUH. Furthermore, we showed that there was no difference between LDUH and LMWH in terms of DVT location, bleeding complications, or rate of discontinuation of prophylaxis. However, high doses of either LDUH or LMWH appeared more effective than low doses.

As DVT prophylaxis gains acceptance as a quality measure and potentially as a Pay for Performance criteria with payers such as Medicare, surgeons may be required to: (1) provide adequate prophylaxis; (2) document the timing of prophylaxis before and after surgery; and (3) monitor outcomes including rates of DVT and PE within 30 days of surgery. The current study demonstrates that documentation of outcomes can vary based on different detection methods. For example, most surgeons use clinical suspicion to prompt an ultrasound examination; however, only two of the 26 RCTs reviewed in this study used this detection method. The majority of published literature on DVT rates utilized routine testing with detection methods that are no longer used (e.g., FUT, venography). Less is known about the rates of postoperative DVT using clinical suspicion to guide further work-up with an ultrasound examination of the lower extremities. In addition, we have shown that the majority of DVTs in patients receiving appropriate pharmacologic prophylaxis are distal. Distal DVTs may have the same risk of postthrombotic syndrome as proximal DVTs, confer an increased risk of future DVTs, and can propagate proximally leading to PEs.1 Unfortunately, clinical exam and ultrasound have poor sensitivity for detecting these distal DVTs. Based on the methodologic challenges associated with DVT detection and measuring outcomes of DVT or PE after hospital discharge, it appears that the most meaningful approach to evaluating quality is adherence to process measures for DVT prophylaxis (e.g., receipt of appropriate DVT prophylaxis before and after surgery). This systematic review suggests that surgical oncology patients should receive prophylaxis with either LMWH or LDUH in combination with mechanical prophylaxis.

Pushback in implementing these findings may be supported by several issues. First, surgeons are often reticent to use pharmacologic DVT prophylaxis for fear of bleeding complications. Our study showed that the published rates of major bleeding complications are low, and should probably not prevent appropriate prophylaxis in the vast majority of patients without significant risk factors for bleeding. A second argument weighing against pharmacologic prophylaxis is that anesthesiologists often resist pharmacologic prophylaxis due to concern over increased risk of spinal hematoma with neuraxial anesthesia; however, this risk may be acceptable. Guidelines from the American Society of Regional Anesthesia (ASRA) allow neuraxial anesthesia use with pharmacologic prophylaxis as long as there is appropriate caution with patient selection as follows: avoiding patients with known clotting disorders, avoiding patients receiving thienopyridine platelet inhibitors (clopidogrel, ticlodipine) within 2 weeks of operation, waiting until trough blood levels of heparin for those already receiving prophylaxis, delaying prophylaxis if a hemorrhagic aspirate is performed, removing epidural catheter 2 h prior to next scheduled heparin injection and waiting 2 h after removal to resume injections, and always monitoring for symptoms of spinal hematoma when using epidural anesthesia and pharmacologic prophylaxis concurrently.32 Finally, there may be a concern with the use of pharmacologic DVT prophylaxis and the possibility of heparin-induced thrombocytopenia (HIT). However, a recent review suggests that HIT (defined as a 50+% decrease in platelet count beginning five or more days after the start of heparin therapy with presence of heparin-dependent IgG antibodies) occurs in 1–5% of patients receiving LDUH and <1% of patients receiving LMWH pro-phylaxis.33 This decreased risk of HIT may justify the added expense of LMWH.

As with all reviews of the literature, there are limitations to this systematic review. These include: a lack of literature on specific types of surgery, biases inherent in systematic reviews, and missing information. "Major general surgery" was used as inclusion criteria by many of these studies, which usually includes abdominal, gynecologic, noncardiac thoracic, and urologic surgery. Most studies did not provide the rate of DVT stratified by the type of the operation, and thus a subgroup analysis based on the type of surgery was not possible. An additional limitation is the potential biases inherent in systematic reviews including language, publication, and citation bias as studies in English or studies with positive findings are more likely to be published and cited. Finally, some RCTs were missing useful information, such as patient demographics, patient risk factors for DVT (e.g., obesity, prior DVT), and anatomic location of the DVT. Nevertheless, at a time when DVT prophylaxis is becoming increasingly evaluated as a potential quality measure, this systematic review examined 26 individual RCTs and pooled the data for DVT rates, prophylaxis efficacy, and bleeding complications in surgical oncology patients.

In summary, surgical oncology patients are a particularly vulnerable group for whom aggressive DVT prophylaxis is imperative. As quality improvement organizations focus on perioperative DVT prophylaxis, hospitals and providers will need to determine appropriate prophylaxis guidelines. This comprehensive systematic review establishes both LDUH and LMWH as equivalent, safe, and effective forms of pharmacologic DVT prophylaxis in surgical oncology patients. In addition, when pharmacologic prophylaxis is used in conjunction with mechanical prophylaxis the efficacy appears to increase. The information in this study can be used by clinicians to provide appropriate and timely prophylaxis for individual patients as well as to create evidence-based guidelines for improved quality of care.


   ACKNOWLEDGMENTS
 
This work was supported by the Robert Wood Johnson Clinical Scholars Program.


   FOOTNOTES
 
Presented at 2006 Society of Surgical Oncology Annual Meeting, San Diego, CA.

Received for publication June 9, 2006. Accepted for publication June 14, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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