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1.  Venous thromboprophylaxis in UK medical inpatients 
We prospectively assessed the implementation of venous thromboembolism (VTE) prophylaxis guidelines and the impact of grand round presentation of the datain changing clinical practice. Two NHS teaching hospitals were studied for 24 months from January 2003. Patients were risk stratified according to the THRIFT (thromboembolic risk factor) consensus group guidelines and compared with the recommendations of the THRIFT and ACCP (American College of Chest Physicians) consensus groups. Six months following presentation of the initial results, a further analysis was made to assess changes in clinical practice.
1128 patients were assessed of whom 1062 satisfied the inclusion criteria for thromboprophylaxis. 89% of all patients were stratified as having high or moderate riskof developing VTE. Of these only 28% were prescribed some form of thromboprophylaxis—4% received the THRIFT-recommended and 22% received the ACCP-recommended thromboprophylaxis. The vast majority (72%) received no thromboprophylaxis at all. Reassessment, following data presentation at grandrounds, showed a significant increase to 31% inpatients receiving THRIFT (P<0.0001) and ACCP (P=0.002) recommended thromboprophylaxis. However,the proportion of patients receiving no form of prophylaxis barely changed (72% to 69%: P=0.59).
We found a gross underutilization of thromboprophylaxis in hospitalized medical patients. A simple grand-round presentation of the data and recommended guidelines to clinicians significantly increased the proportion of patients receiving recommended thromboprophylaxis but did not increasethe overall proportion of patients receiving it. Wetherefore conclude that a single presentation of guidelines is not enough to achieve the desired levels. Such presentations may only serve to make DVT (deepvenous thromboembolism) aware clinicians prescribe prophylaxis more accurately.
PMCID: PMC1275999  PMID: 16260800
2.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
PMCID: PMC3445446  PMID: 23028261
3.  A cohort study on the incidence and outcome of pulmonary embolism in trauma and orthopedic patients 
BMC Medicine  2014;12:39.
This study aims to determine the incidence of pulmonary embolism (PE) in trauma and orthopedic patients within a regional tertiary referral center and its association with the pattern of injury, type of treatment, co-morbidities, thromboprophylaxis and mortality.
All patients admitted to our institution between January 2010 and December 2011, for acute trauma or elective orthopedic procedures, were eligible to participate in this study. Our cohort was formed by identifying all patients with clinical features of PE who underwent Computed Tomography-Pulmonary Angiogram (CT-PA) to confirm or exclude the clinical suspicion of PE, within six months after the injury or the surgical procedure.
Case notes and electronic databases were reviewed retrospectively to identify each patient’s venous thromboembolism (VTE) risk factors, type of treatment, thromboprophylaxis and mortality.
Out of 18,151 patients admitted during the study period only 85 (0.47%) patients developed PE (positive CT-PA) (24 underwent elective surgery and 61 sustained acute trauma). Of these, only 76% of the patients received thromboprophylaxis. Hypertension, obesity and cardiovascular disease were the most commonly identifiable risk factors. In 39% of the cases, PE was diagnosed during the in-hospital stay. The median time of PE diagnosis, from the date of injury or the surgical intervention was 23 days (range 1 to 312). The overall mortality rate was 0.07% (13/18,151), but for those who developed PE it was 15.29% (13/85). Concomitant deep venous thrombosis (DVT) was identified in 33.3% of patients. The presence of two or more co-morbidities was significantly associated with the incidence of mortality (unadjusted odds ratio (OR) = 3.52, 95% confidence interval (CI) (1.34, 18.99), P = 0.034). Although there was also a similar clinical effect size for polytrauma injury on mortality (unadjusted OR = 1.90 (0.38, 9.54), P = 0.218), evidence was not statistically significant for this factor.
The incidence of VTE was comparable to previously reported rates, whereas the mortality rate was lower. Our local protocols that comply with the National Institute for Health and Clinical Excellence (NICE) guidelines in the UK appear to be effective in preventing VTE and reducing mortality in trauma and orthopedic patients.
PMCID: PMC3996019  PMID: 24589368
Pulmonary embolism; Deep venous thrombosis; Trauma; Orthopedic surgery; Arthroplasty; Mortality; Incidence
4.  Is routine thromboprophylaxis justified among Indian patients sustaining major orthopedic trauma? A systematic review 
Indian Journal of Orthopaedics  2011;45(3):197-207.
Venous thromboembolism (VTE) is one of the most common preventable cause of morbidity and mortality after trauma. Though most of the western countries have their guidelines for thromboprophylaxis in these patients, India still does not have these. The increasing detection of VTE among Indian population, lack of awareness, underestimation of the risk, and fear of bleeding complications after chemical prophylaxis have made deep vein thrombosis (DVT) a serious problem, hence a standard guideline for thromboprophylaxis after trauma is essential. The present review article discusses the incidence of DVT and role of thromboprophylaxis in Indian patients who have sustained major orthopedic trauma. A thorough search of ‘PubMed’ and ‘Google Scholar’ revealed 10 studies regarding venous thromboembolism in Indian patients after major orthopedic trauma surgery (hip or proximal femur fracture and spine injury). Most of these studies have evaluated venous thromboembolism in patients of arthroplasty and trauma. The incidence, risk factors, diagnosis and management of VTE in the subgroup of trauma patients (1049 patients) were separately evaluated after segregating them from the arthroplasty patients. Except two studies, which were based on spinal injury, all other studies recommended screening/ thromboprophylaxis in posttraumatic conditions in the Indian population. Color Doppler was used as common diagnostic or screening tool in most of the studies (eight studies, 722 patients). The incidence of VTE among thromboprophylaxis-receiving group was found to be 8% (10/125), whereas it was much higher (14.49%, 40/276) in patients not receiving any form of prophylaxis. Indian patients have definite risk of venous thromboembolism after major orthopedic trauma (except spinal injury), and thromboprophylaxis either by chemical or mechanical methods seems to be justified in them.
PMCID: PMC3087220  PMID: 21559098
Thromboprophylaxis; trauma; venous thromboembolism
5.  Risk factors and distribution of symptomatic venous thromboembolism in total hip and knee replacements: prospective study 
International Orthopaedics  2012;36(6):1299-1305.
Venous thromboembolism (VTE) is a common complication of orthopaedic surgery in the industrialised world; though there may be variability between population groups. This study aims to define the incidence and risk factors for symptomatic VTE following primary elective total hip and knee arthoplasty surgery in a single centre in Eastern Europe.
This prospective study included 499 adult patients undergoing total hip and knee arthroplasty for symptomatic osteoarthritis over a two-year period at the Clinic of Orthopaedic Surgery and Traumatology, Belgrade.
The overall rate of confirmed symptomatic VTE during hospitalisation was 2.6%. According to the univariate logistic regression, an age greater than 75 years (OR = 3.08; 95%CI = 1.01–9.65), a family history of VTE (OR = 6.61; 95% CI = 1.33–32.90), varicose veins (OR = 3.13; 95% CI = 1.03–9.48), and ischemic heart disease (OR = 4.93; 95% CI = 1.61–15.09) were significant risk factors for in-hospital VTE. A family history of VTE and ischemic heart disease were independent risk factors according to multivariate regression analysis. Preoperative initiation of pharmacological thromboprophylaxis (p = 0.03) and a longer duration of thromboprophylaxis (p = 0.001) were protective for postoperative DVT. Though thromboprophylaxis was safe, with very few patients suffering major haemorrhage or heparin-induced thrombocytopenia, there was a general reluctance by our local surgeons to use prolonged thromboprophylaxis.
VTE is common following hip and knee arthroplasty surgery. Orthopaedic patients with a family history of VTE, heart failure and coronary heart disease are at a considerable risk of thromboembolic complications in the postoperative period. There may be a role for preoperative thromboprophylaxis in addition to prolonged postoperative treatment.
PMCID: PMC3353084  PMID: 22215369
6.  Venous Thromboembolism in Patients with Diabetes Mellitus 
The American journal of medicine  2012;125(7):709-716.
The majority of epidemiological studies demonstrate an increased risk of venous thromboembolism among diabetic patients. Our aim was to compare clinical characteristics, prophylaxis, treatment, and outcomes of venous thromboembolism in patients with and without previously diagnosed diabetes.
We studied diabetic patients in the population-based Worcester Venous Thromboembolism Study of 2488 consecutive patients with validated venous thromboembolism.
Of 2488 venous thromboembolism patients, 476 (19.1%) had a clinical history of diabetes. Thromboprophylaxis was omitted in more than one third of diabetic patients who had been hospitalized for non-venous-thromboembolism-related illness or had undergone major surgery within 3 months before diagnosis. Patients with diabetes were more likely than nondiabetic patients to have a complicated course after venous thromboembolism. Patients with diabetes were more likely than patients without diabetes to suffer recurrent deep vein thrombosis (14.9% vs 10.7%) and long-term major bleeding complications (16.4% vs 11.7%) (all P = .01). Diabetes was associated with a significant increase in the risk of recurrent deep vein thrombosis (adjusted odds ratio [AOR] 1.74; 95% confidence interval [CI], 1.21–2.51). Aspirin therapy at discharge (AOR 1.59; 95% CI, 1.1–2.3) and chronic kidney disease (AOR 2.19; 95% CI, 1.44–3.35) were independent predictors of long-term major bleeding.
Patients with diabetes who developed venous thromboembolism were more likely to suffer a complicated clinical course. Diabetes was an independent predictor of recurrent deep vein thrombosis. We observed a low rate of thromboprophylaxis in diabetic patients. Further studies should focus on venous thromboembolism prevention in this vulnerable population.
PMCID: PMC3424058  PMID: 22560173
Deep vein thrombosis; Diabetes mellitus; Prophylaxis; Pulmonary embolism; Treatment; Venous thromboembolism
7.  Thromboprophylaxis in spinal surgery: a survey 
Venous Thromboembolism (VTE) is the most common complication following major joint surgery. While attention has been focused upon the incidence of thromboembolic disease following total hip or knee arthroplasty or emergency surgery for hip fracture, there exists a gap in the medical literature examining the incidence of VTE in spinal surgery. Evidence suggests that the prevalence of DVT after spinal surgery is higher than generally recognized but with a shortage of epidemiological data, guidelines for optimal prophylaxis are limited. This survey, of individuals attending the 2009 British Association of Spinal Surgeons Annual Meeting, sought to examine prevailing trends in VTE thromboprophylaxis in spinal surgery, adherence to guideline outlined by the National Institute for Health and Clinical Excellence (NICE) and to compare selections made by orthopaedic and neurosurgeons.
We developed a questionnaire with eight clinical scenarios. Participants were asked to supply details on their specialty and to select which method(s) of thromboprophylaxis they would employ for each scenario. Chi squared analysis was used for statistical comparison of the questionnaire responses.
73% of neurosurgical respondents' and 31% of orthopaedic surgeons employed low molecular weight heparin (p < 0.001). Neurosurgeons also selected anti-embolism stockings more frequently (79% v 50%) while orthopaedic surgeons preferred mechanical prophylaxis (26% v 9%). There was no significant difference between trauma and non-trauma scenarios (p = 0.05).
There is no clear consensus in thromboprophylaxis in spinal surgery. There was a significant difference in selections across surgical disciplines with neurosurgeons more closely adhering to national guidelines. Further research examining the epidemiology of venous thromboembolism in spinal surgery and the risks-benefit relationship of thromboprophylaxis is warranted.
PMCID: PMC3349591  PMID: 22458927
Spinal surgery; Venous thromboembolism; Thromboprophylaxis; Orthopaedic surgery; Neurosurgery
8.  Lack of Clinical Benefit of Thromboprophylaxis in Patients Hospitalized in a Medical Unit Over a 10-year Span 
Thromboprophylaxis for hospitalized patients with a high risk of venous thromboembolic events (VTEs) is strongly recommended but is not universally applied on medical units. Outside of randomized trials, there is minimal evidence that the usual medications reduce the incidence of clinically significant VTE.
We conducted a retrospective cohort study including all patients admitted into a teaching medical unit during years 2001-2002, 2003-2004, 2005-2006, 2007-2008 and 2009-2010. Inclusion criteria for the analysis were having one or more risk factors for a VTE and no contraindication to thromboprophylaxis.
Of 2,369 patients reviewed, 1,302 satisfied the inclusion criteria. Between years 2001-2002 and 2009-2010, the proportion of patients receiving thromboprophylaxis increased from 29.2% to 76.4% (P < 0.0001) and the duration of thromboprophylaxis increased from 63% of hospital stay to 84% (P = 0.004). There was no statistically significant association between the number of risk factors and the rate of thromboprophylaxis. Overall, only 32 patients suffered from a VTE with no decrease in VTE incidence between years 2001-2002 and 2009-2010. A total of 107 patients had a bleeding event, and there was no statistically significant change in the incidence of bleeding during our study period.
In our medical units, we found a statistically significant increase in the use of the thromboprophylaxis practice. However, this was not associated with any statistically significant impact on the VTE incidence. This suggests that patients given thromboprophylaxis could be better selected.
PMCID: PMC3935529  PMID: 24578750
Thromboprophylaxis; Deep vein thrombosis; Pulmonary embolus; Anticoagulation; Hospital medicine
9.  Symptomatic venous thromboembolism and mortality in orthopaedic surgery – an observational study of 45 968 consecutive procedures 
Little information exists on the presentation of symptomatic venous thromboembolism (VTE) in orthopaedic surgery when a defined protocol for thromboprophylaxis is used. The objective with this study was to establish the VTE rate and mortality rate in orthopaedic surgery.
We performed a prospective, single centre observational cohort study of 45 968 consecutive procedures in 36 388 patients over a 10 year period. Follow-up was successful in 99.3%. The primary study outcome was the incidence of symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and mortality at 6 weeks, specified for different surgical procedures. The secondary outcome was to describe the DVT distribution in proximal and distal veins and the proportion of VTEs diagnosed after hospital discharge. For validation purposes, a retrospective review of VTEs diagnosed 7–12 weeks postoperatively was also performed.
In total, 514 VTEs were diagnosed (1.1%; 95% CI: 1.10-1.14), the majority (84%) after hospital discharge (432 out of 514).With thromboprophylaxis, high incidence of VTE was found after internal fixation (IF) of pelvic fracture (12%; 95% CI: 5–26), knee replacement surgery (3.7%; 95% CI: 2.8-5.0), after internal fixation (IF) of proximal tibia fracture (3.8%; 95% CI: 2.3-6.3) and after IF of ankle fracture (3.6%; 95% CI: 2.9-4.4). Without thromboprophylaxis, high incidence of VTE was found after Achilles tendon repair (7.2%; 95% CI: 5.5-9.4). In total 1094 patients deceased (2.4%; 95% confidence interval (CI): 2.33- 2.44) within 6 weeks of surgery. Highest mortality was seen after lower limb amputation (16.3%, CI: 13.8-19.1) and after hip hemiarthroplasty due to hip fracture (9.6%, CI; 7.6-12.1).
The overall incidence of VTE is low after orthopaedic surgery but our study highlights surgical procedures after which the risk for VTE remains high and improved thromboprophylaxis is needed.
PMCID: PMC3682916  PMID: 23734770
Deep vein thrombosis; Mortality; Operation; Orthopaedic surgery; Prophylaxis; Pulmonary embolism; Thrombosis; Venous thromboembolism
10.  Are hospitals delivering appropriate VTE prevention? The venous thromboembolism study to assess the rate of thromboprophylaxis (VTE start) 
The 7th conference of the American College of Chest Physicians (ACCP7) provides recommendations on the type, dose, and duration of thromboprophylaxis in hospitalized patients at risk of venous thromboembolism (VTE), but the extent to which hospitals follow these criteria has not been well studied. Discharge and billing records for patients admitted to any of 16 acute-care hospitals from January 2005 to December 2006 were obtained. Patients 18 years or older who had an inpatient stay ≥2 days and no apparent contraindications for thromboprophylaxis were grouped into the categories of critical care, surgery and medically ill before being assessed for additional VTE risk factors based on the diagnostic criteria outlined in ACCP7. For patients at risk, the recommended type (mechanical or pharmacologic), dose, and duration of thromboprophylaxis was identified based on the guidelines and compared to the regimen actually received, if any. Among the 258,556 hospitalized patients, 68,278 (26.4%) were determined to be at risk of VTE without apparent contraindications for thromboprophylaxis. The proportions of patients who received the appropriate type, dose, and duration of thromboprophylaxis were 10.5, 9.8, and 17.9% for critical care, medical, and surgical patients, respectively. Of those at risk, 36.8% received no thromboprophylaxis and an additional 50.2% received thromboprophylaxis deemed inappropriate for one or more reasons. The implementation of ACCP7 guidelines for type, dosage, and duration of thromboprophylaxis is low in patients at risk of VTE. There is a need for physicians and health systems to improve awareness and implementation of recommended thromboprophylaxis.
PMCID: PMC2837191  PMID: 19548071
Venous thromboembolism; Guidelines; Health care quality
11.  Adherence to local guidelines for venous thromboprophylaxis: a cross-sectional study of medical inpatients in Argentina 
Thrombosis Journal  2011;9:18.
Venous thromboembolism prophylaxis has been shown to safely and cost-effectively reduce the incidence of thromboembolic events in medical inpatients. However, there is a gap between evidence and medical practice. The aim of this study was evaluate the appropriateness of prescribing venous thromboembolism prophylaxis in accordance with local recommendations for medical inpatients.
This cross-sectional study included 310 prescriptions of medical general-ward admitted patients of two university hospitals of Buenos Aires, Argentina.
Data was collected using filled-out prescriptions, medical records and interviews with the head attending physician. Information was gathered at different times during 16 days randomly selected over September 2007 and January 2008.
One hundred eighty eight patients' prescriptions (60.6%) were appropriate according to the institutional guidelines. Inappropriateness was due to excessive (14.2%), insufficient (15.8%) and absent (9.4%) prescribing. According to the recommendations of the American College of Chest Physicians, 256 (82.6%) patients received appropriate prophylaxis. Twenty-nine patients (9.4%) were considered at low risk for thromboembolism and did not need pharmacologic or mechanical prophylaxis. One hundred three patients (33.2%) had at least one major risk factor for venous thromboembolism. Compliance with the institutional guidelines was more frequently in the case of high risk patients. Complex preventive measures and low risk patients were related to lower adherence to recommendations. In the multivariate analysis, predictors of inappropriateness were the requirement of a surgical procedure and absence of prophylaxis prescribing at admission. In contrast, patients with a diagnosis of gastrointestinal disorders had lower odds of inappropriateness than those with an infectious disease.
Most medical inpatients received some thromboprophylaxis measure, but the compliance with recommendations was less frequent. Efforts should be made to improve the appropriate prescription.
PMCID: PMC3286366  PMID: 22172213
12.  Comparative study of extended versus short term thromboprophylaxis in patients undergoing elective total hip and knee arthroplasty in Indian population 
Indian Journal of Orthopaedics  2013;47(2):161-167.
Postoperative thromboprophylaxis with low molecular weight heparin (LMWH) for an extended period of 4 weeks is now preferred over short term thromboprophylaxis in patients undergoing total hip/knee arthroplasty (THA/TKA). However, most of the data demonstrating the efficacy and safety of extended thromboprophylaxis and short term thromboprophylaxis is from clinical trials done in the West. In India, the data of the incidence of venous thromboembolism (VTE) following THA/TKA has been conflicting and the duration has not been clearly defined. The aim of the study was to evaluate and compare the efficacy of extended thromboprophylaxis over short term thromboprophylaxis in Indian patients undergoing elective THA/TKA surgeries.
Materials and Methods:
A prospective arm of 197 consecutive patients undergoing elective THA/TKA surgeries who were administered extended thromboprophylaxis for 4 weeks was compared with a historical group of 795 patients who were administered short term thromboprophylaxis for only 7-11 days. In both groups, LMWH (enoxaparin) was used in a dose of 40 mg subcutaneously, in addition to mechanical thromboprophylaxis. Primary efficacy endpoint was objectively confirmed venous thromboembolism (VTE). The presence of DVT was confirmed by a combination of pretest scoring, D-dimer, and Color Doppler Flow Imaging (CDFI) of deep veins of the legs, and pulmonary thromboembolism (PTE) was confirmed by ventilation perfusion (V/Q) scan or pulmonary angiography. Fisher's exact test and t test were used for the statistical analysis. The baseline confounding factors were compared between the two groups using t test for comparing the means for continuous data and Fisher's exact test for categorical data.
In the prospective arm, only 1 patient developed symptomatic PTE compared to 26 (3.27%) cases of VTE (20 cases of PTE and 6 cases of DVT) in the retrospective group.
Extended thromboprophylaxis (for 4 weeks) was found to be more effective than short term thromboprophylaxis in minimizing the risk of postoperative VTE in patients who underwent THA/TKA.
PMCID: PMC3654466  PMID: 23682178
Deep vein thromboembolism; LMWH; pulmonary embolism; thromboprophylaxis; venous thromboembolism
13.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
PMCID: PMC2695771  PMID: 19554085
14.  Outcomes of thromboprophylaxis with enoxaparin vs. unfractionated heparin in medical inpatients 
Thrombosis Journal  2006;4:17.
Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients.
To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice.
Using a large, multi-hospital, US database, we identified persons aged ≥40 years hospitalized for ≥6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups.
We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.
PMCID: PMC1624807  PMID: 17005045
15.  New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders 
Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, is a major challenge for health care systems. It is the third most common vascular disease after coronary heart disease and stroke, and many hospitalized patients have at least one risk factor. In particular, patients undergoing hip or knee replacement are at risk, with an incidence of asymptomatic deep vein thrombosis of 40%–60% without thromboprophylaxis. Venous thromboembolism is associated with significant mortality and morbidity, with patients being at risk of recurrence, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Arterial thromboembolism is even more frequent, and atrial fibrillation, the most common embolic source (cardiac arrhythmia), is associated with a five-fold increase in the risk of stroke. Strokes due to atrial fibrillation tend to be more severe and disabling and are more often fatal than strokes due to other causes. Currently, recommended management of both venous and arterial thromboembolism involves the use of anticoagulants such as coumarin and heparin derivatives. These agents are effective, although have characteristics that prevent them from providing optimal anticoagulation and convenience. Hence, new improved oral anticoagulants are being investigated. Dabigatran is a reversible, direct thrombin inhibitor, which is administered as dabigatran etexilate, the oral prodrug. Because it is the first new oral anticoagulant that has been licensed in many countries worldwide for thromboprophylaxis following orthopedic surgery and for stroke prevention in patients with atrial fibrillation, this compound will be the main focus of this review. Dabigatran has been investigated for the treatment of established venous thromboembolism and prevention of recurrence in patients undergoing hip or knee replacement, as well as for stroke prevention in atrial fibrillation patients with a moderate and high risk of stroke.
PMCID: PMC3273411  PMID: 22323896
dabigatran etexilate; venous thromboembolism; stroke; prevention; treatment
16.  The Worcester Venous Thromboembolism Study A Population-Based Study of the Clinical Epidemiology of Venous Thromboembolism 
While there have been marked advances in diagnostic and therapeutic strategies for venous thromboembolism, our understanding of its clinical epidemiology is based on studies conducted more than a decade ago.
The purpose of this observational study was to describe the incidence and attack rates of venous thromboembolism in residents of the Worcester Statistical Metropolitan Area in 1999. We also describe demographic and clinical characteristics, management strategies, and associated hospital and 30-day outcomes.
The medical records of all residents from Worcester, MA (2000 census = 477,800), diagnosed with International Classification of Diseases, 9th revision (ICD-9) codes consistent with possible venous thromboembolism during 1999 were independently validated, classified, and reviewed by trained abstractors.
A total of 587 subjects were enrolled with validated venous thromboembolism. The incidence and attack rates of venous thromboembolism were 104 and 128 per 100,000 population, respectively. Three quarters of patients developed their venous thromboembolism in the outpatient setting – a substantial proportion of these patients had undergone recent surgery or had a recent prior hospitalization. Less than half of the patients received anticoagulant prophylaxis during high-risk periods before their venous thromboembolism. Thirty-day rates of venous thromboembolism recurrence, major bleeding, and mortality were 4.8%, 7.7%, and 6.6%, respectively.
These data provide insights into recent incidence and attack rates, changing patient profiles, management strategies, and subsequent outcomes in patients with venous thromboembolism. The underutilization of prophylaxis before venous thromboembolism, and relatively high 30-day recurrence rates, suggest a continued need for the improvement of venous thromboembolism prophylaxis and management in the community.
PMCID: PMC1924694  PMID: 16808773
venous thromboembolism; deep vein thrombosis; pulmonary embolism; population-health
17.  Risk of venous thromboembolism and benefits of prophylaxis use in hospitalized medically ill US patients up to 180 days post-hospital discharge 
Thrombosis Journal  2011;9:15.
To assess the incidence of venous thromboembolism (VTE) and bleeding events with or without thromboprophylaxis and the associated costs in a cohort of medically ill patients in both in-hospital and outpatient settings.
A large hospital drug database and linked outpatient files were used to identify patients eligible for this analysis, based on demographic and clinical characteristics.
Among 11,135 patients identified, 1592 (14.30%) were admitted with chronic heart failure, 1684 (15.12%) with thromboembolic stroke, 3834 (34.43%) with severe lung disease, 1658 (14.89%) with acute infection, and 2367 (21.26%) with cancer. Of the 11,135 patients, 5932 received anticoagulant therapy at some point during their hospitalization and until 30 days after discharge. VTE events occurred in 1.30% of patients who received anticoagulant prophylaxis versus 2.99% of patients who did not. Risk-adjusted total healthcare costs for patients with a VTE or major or minor bleeding event were significantly higher than for those without events (VTE: $52,157 ± 24,389 vs $24,164 ± 11,418; major bleeding: $33,656 ± 18,196 vs $24,765 ± 11,974; minor bleeding: $33,690 ± 14,398 vs $23,610 ± 11,873). In a multivariate analysis, appropriate anticoagulant prophylaxis use was significantly associated with a reduced risk of clinical VTE, compared with no anticoagulant use (hazard ratio: 0.37). Patients admitted with thromboembolic stroke were less likely to have a VTE than patients admitted with cancer (hazard ratio: 0.42).
In this analysis, VTE and major bleeding event rates were lower for patients who received prophylaxis compared with those who did not. Prophylaxis use was associated with lower healthcare costs.
PMCID: PMC3215634  PMID: 21995820
18.  Thromboprophylaxis in surgical patients 
Canadian Journal of Surgery  2003;46(2):129-135.
Venous thromboembolism is the most common preventable cause of death in surgical patients. Thromboprophylaxis, using mechanical methods to promote venous outflow from the legs and antithrombotic drugs, provides the most effective means of reducing morbidity and mortality in these patients. Despite the evidence supporting thromboprophylaxis, it remains underused because surgeons perceive that the risk of venous thromboembolism is not high enough to justify the potential hemorrhagic complications of anticoagulant use. The risk of venous thromboembolism is determined by patient characteristics and by the type of surgery that is performed. In this paper we identify the risk factors for venous thromboembolism and provide a scheme for stratifying surgical patients according to their risk. We describe the mechanism of action of the various forms of thromboprophylaxis and outline the evidence supporting thromboprophylaxis in different surgical settings. Finally, we recommend optimal forms of thromboprophylaxis in patients who undergo various types of surgery. Intermittent pneumatic compression, with or without elastic stockings, can be used for thromboprophylaxis in patients who undergo neurosurgical procedures; for patients who undergo vascular or cardiovascular procedures, long-term acetylsalicylic acid should be used for thromboprophylaxis. Low-molecular-weight heparin (LMWH) or warfarin is the choice for patients with spinal cord operations and all patients with major trauma who do not have contraindications to anticoagulation should receive thromboprophylaxis with LMWH.
PMCID: PMC3211697  PMID: 12691354
19.  Prevention of Venous Thromboembolism in Hospitalized Patients With Cancer 
Journal of Clinical Oncology  2009;27(29):4874-4880.
This is a literature review of the frequency of venous thromboembolism in hospitalized patients with cancer and of the available evidence supporting the use of thromboprophylaxis. Patients with cancer are at particularly high risk of venous thromboembolism and account for almost 20% of patients in the population. Hospitalization is an important risk factor in patients with cancer, with rates reported between 0.6% and 7.8%. The incidence has been increasing over the past decade. Three randomized controlled trials and meta-analyses indicate that prophylaxis with low molecular weight heparin, heparin, or fondaparinux significantly reduces the rate of venous thromboembolism in hospitalized medical patients who are at high risk. Patients with cancer were included in these studies, but prospective trials specifically focused on patients with cancer are not available. Evidence indicates that appropriate thromboprophylaxis is provided to a minority of hospitalized patients with cancer and that targeted educational efforts and computerized prompt systems can increase appropriate use. Guidelines developed by both oncology and thrombosis organizations support the use of thromboprophylaxis in hospitalized patients with cancer. In conclusion, most patients hospitalized with cancer are at high risk of venous thromboembolism, and thromboprophylaxis should be provided in the absence of active bleeding or a high bleeding risk.
PMCID: PMC2764393  PMID: 19704060
20.  Risk of first venous thromboembolism in pregnant women in hospital: population based cohort study from England 
Objective To examine the potential for preventing venous thromboembolism during and after antepartum hospital admissions in pregnant women.
Design Cohort study using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records.
Setting Primary and secondary care centres, England.
Participants 206 785 women aged 15-44 who had one or more pregnancies from1997 up to 2010.
Main outcome measure Risk of first venous thromboembolism in pregnant women admitted to hospital for one or more days for reasons other than delivery or venous thromboembolism. Risk was assessed by calculating the absolute rate of venous thromboembolism and comparing these rates with those observed during follow-up time not associated with hospital admission using a Poisson regression model to estimate incidence rate ratios.
Results Admission to hospital in pregnancy was associated with an increased risk of venous thromboembolism (absolute rate 1752/100 000 person years; incidence rate ratio 17.5, 95% confidence interval 7.69 to 40.0) compared with time outside hospital. The rate of venous thromboembolism was also high during the 28 days after discharge (absolute rate 676; 6.27, 3.74 to 10.5). The rate during and after admission combined was highest in the third trimester (961; 5.57, 3.32 to 9.34) and in those aged ≥35 years (1756; 21.7, 9.62 to 49.0). While the absolute rate in the combined period was highest for those with three or more days in hospital (1511; 12.2, 6.65 to 22.7), there was also a fourfold increase (558; 4.05, 2.23 to 7.38) in the risk of venous thromboembolism for those admitted to hospital for less than three days.
Conclusion The overall risk of first venous thromboembolism in pregnant women increased during admissions to hospital not related to delivery, and remained significantly higher in the 28 days after discharge. During these periods need for thromboprophylaxis should receive careful consideration.
PMCID: PMC3898207  PMID: 24201164
21.  Postdischarge thromboprophylaxis and mortality risk after hip-or knee-replacement surgery 
Patients undergoing hip or knee replacement are at high risk of developing a postoperative venous thromboembolism even after discharge from hospital. We sought to identify hospital and patient characteristics associated with receiving thromboprophylaxis after discharge and to compare the risk of short-term mortality among those who did or did not receive thromboprophylaxis.
We conducted a retrospective cohort study using system-wide hospital discharge summary records, physician billing information, medication reimbursement claims and demographic records. We included patients aged 65 years and older who received a hip or knee replace ment and who were discharged home after surgery.
In total we included 10 744 patients. Of these, 7058 patients who received a hip replacement and 3686 who received a knee replacement. The mean age was 75.4 (standard deviation [SD] 6.8) years and 38% of patients were men. In total, 2059 (19%) patients received thomboprophylaxis at discharge. Patients discharged from university teaching hospitals were less likely than those discharged from community hospitals to received thromboprophylaxis after discharge (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80–1.00). Patients were less likely to receive thromboprophylaxis after discharge if they had a longer hospital stay (15–30 days v. 1–7 days, OR 0.69, 95% CI 0.59–0.81). Patients were more likely to receive thromboprophylaxis if they had hip (v. knee) replacement, osteoarthritis, heart failure, atrial fibrillation or hypertension, higher (v. lower) income or if they were treated at medium-volume hospitals (69–116 hip and knee replacements per year). In total, 223 patients (2%) died in the 3-month period after discharge. The risk of short-term mortality was lower among those who received thromboprophylaxis after discharge (hazard ratio [HR] 0.34, 95% CI 0.20–0.57).
Fewer than 1 in 5 elderly patients discharged home after a hip-or knee-replacement surgery received postdischarge thromboprophylaxis. Those prescribed these medications had a lower risk of short-term mortality. The benefits of and barriers to thromboprophylaxis therapy after discharge in this population requires further study.
PMCID: PMC2396368  PMID: 18519902
22.  Venous Thromboembolism Risk in Patients With Cancer Receiving Chemotherapy: A Real-World Analysis 
The Oncologist  2013;18(12):1321-1329.
The occurrence of malignant disease increases the risk for venous thromboembolism (VTE). This study sought to evaluate the risk for VTE in a large unselected cohort of patients with cancer receiving chemotherapy. Those undergoing chemotherapy as outpatients are at high risk for VTE and for major bleeding complications, and thromboprophylaxis should be considered for these patients.
The occurrence of malignant disease increases the risk for venous thromboembolism (VTE). Here we evaluate the risk for VTE in a large unselected cohort of patients with cancer receiving chemotherapy.
The United States IMPACT health care claims database was retrospectively analyzed to identify patients with a range of solid tumors who started chemotherapy from January 2005 through December 2008. International Classification of Diseases, 9th revision, Clinical Modification Codes were used to identify cancer location, presence of VTE 3.5 months and 12 months after starting chemotherapy, and incidence of major bleeding complications. Health care costs were assessed one year before initiation of chemotherapy and one year after initiation of chemotherapy.
The overall incidence of VTE 3.5 months after starting chemotherapy was 7.3% (range 4.6%–11.6% across cancer locations) rising to 13.5% at 12 months (range 9.8%–21.3%). The highest VTE risk was identified in patients with pancreatic, stomach, and lung cancer. Patients in whom VTE developed had a higher risk for major bleeding at 3.5 months and at 12 months (11.0% and 19.8% vs. 3.8% and 9.6%, respectively). Health care costs were significantly higher in patients in whom VTE developed.
Those undergoing chemotherapy as outpatients are at increased risk for VTE and for major bleeding complications. Thromboprophylaxis may be considered for such patients after carefully assessing the risks and benefits of treatment.
PMCID: PMC3868427  PMID: 24212499
Cancer; Chemotherapy; Health care costs; Thromboprophylaxis; Venous thromboembolism
23.  Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis 
Objective To determine the effect of sex on the risk of recurrent venous thromboembolism in all patients and in patients with venous thromboembolism that was unprovoked or provoked (by non-hormonal factors).
Data source Comprehensive search of electronic databases (Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials) until July 2010, supplemented by review of conference abstracts and contact with content experts.
Study selection Seven prospective studies investigating an association between D-dimer, measured after anticoagulation was stopped, and disease recurrence in patients with venous thromboembolism.
Data extraction Patient level databases were obtained, transferred to a central database, checked, and completed with further information provided by authors.
Data synthesis 2554 patients with a first venous thromboembolism had follow-up for a mean of 27.1 (SD 19.6) months. The one year incidence of recurrent venous thromboembolism was 5.3% (95% confidence interval 4.1% to 6.7%) in women and 9.5% (7.9% to 11.4%) in men, and the three year incidence of recurrence was 9.1% (7.3% to 11.3%) in women and 19.7% (16.5% to 23.4%) in men. Among patients with unprovoked venous thromboembolism, men had a higher risk of recurrence than did women (hazard ratio 2.2, 95% confidence interval 1.7 to 2.8). After adjustment for women with hormone associated initial venous thromboembolism, the risk of recurrence remained higher in men (hazard ratio 1.8, 1.4 to 2.5). In patients with provoked venous thromboembolism, occurring after exposure to a major risk factor, recurrence of disease did not differ between men and women (hazard ratio 1.2, 0.6 to 2.4). In women with hormone associated venous thromboembolism and no other risk factors, recurrence was lower than that in women with unprovoked venous thromboembolism and no previous hormone use (hazard ratio 0.5, 0.3 to 0.8).
Conclusion In patients with a first unprovoked venous thromboembolism, men have a 2.2-fold higher risk of recurrent venous thromboembolism than do women, which remained 1.8-fold higher in men after adjustment for previous hormone associated venous thromboembolism in women. In patients with a first provoked venous thromboembolism, risk of recurrence does not differ between men and women with or without hormone associated venous thromboembolism. Indefinite anticoagulation may be given greater consideration in men than in women after a first venous thromboembolism.
PMCID: PMC3044449  PMID: 21349898
24.  The Absolute Risk of Venous Thrombosis after Air Travel: A Cohort Study of 8,755 Employees of International Organisations 
PLoS Medicine  2007;4(9):e290.
The risk of venous thrombosis is approximately 2- to 4-fold increased after air travel, but the absolute risk is unknown. The objective of this study was to assess the absolute risk of venous thrombosis after air travel.
Methods and Findings
We conducted a cohort study among employees of large international companies and organisations, who were followed between 1 January 2000 and 31 December 2005. The occurrence of symptomatic venous thrombosis was linked to exposure to air travel, as assessed by travel records provided by the companies and organisations. A long-haul flight was defined as a flight of at least 4 h and participants were considered exposed for a postflight period of 8 wk. A total of 8,755 employees were followed during a total follow-up time of 38,910 person-years (PY). The total time employees were exposed to a long-haul flight was 6,872 PY. In the follow-up period, 53 thromboses occurred, 22 of which within 8 wk of a long-haul flight, yielding an incidence rate of 3.2/1,000 PY, as compared to 1.0/1,000 PY in individuals not exposed to air travel (incidence rate ratio 3.2, 95% confidence interval 1.8–5.6). This rate was equivalent to a risk of one event per 4,656 long-haul flights. The risk increased with exposure to more flights within a short time frame and with increasing duration of flights. The incidence was highest in the first 2 wk after travel and gradually decreased to baseline after 8 wk. The risk was particularly high in employees under age 30 y, women who used oral contraceptives, and individuals who were particularly short, tall, or overweight.
The risk of symptomatic venous thrombosis after air travel is moderately increased on average, and rises with increasing exposure and in high-risk groups.
In a cohort study of 8,755 employees of large international organizations followed for 38,910 person-years, Suzanne Cannegieter and colleagues find a risk of one thrombosis per 4,656 long-haul flights.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying the brain and other vital organs with oxygen and nutrients. When an injury occurs, proteins called clotting factors make the blood gel or coagulate at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood to the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the deep veins of the leg) include pain, swelling, and redness in one leg. DVT is usually treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called pulmonary embolism (PE). Fortunately, DVT and PE are rare but having an inherited blood clotting disorder, taking an oral contraceptive, and some types of surgery are all risk factors for them. In addition, long-haul plane travel increases the risk of DVT and PE, known collectively as venous thrombosis (VT) 2- to 4-fold, in part because the enforced immobilization during flights slows down blood flow.
Why Was This Study Done?
Although the link between air travel and VT was first noticed in the 1950s, exactly how many people will develop DVT and PE (the absolute risk of developing VT) after a long flight remains unknown. This information is needed so that travelers can be given advice about their actual risk and can make informed decisions about trying to reduce that risk by, for example, taking small doses of anticoagulant medicine before a flight. In this study, the researchers have determined the absolute risk of VT during and after long-haul air travel in a large group of business travelers.
What Did the Researchers Do and Find?
The researchers enrolled almost 9,000 employees from several international companies and organizations and followed them for an average of 4.4 years. The details of flights taken by each employee were obtained from company records, and employees completed a Web-based questionnaire about whether they had developed VT and what risk factors they had for the condition. Out of 53 thrombi that occurred during the study, 22 occurred within eight weeks of a long-haul flight (a flight of more than four hours). From this and data on the total time employees spent on long-haul flights, the researchers calculated that these flights tripled the risk of developing VT, and that the absolute risk (the probability of something occurring in a certain time period) of a VT occurring shortly after such travel was one event per 4,656 flights. They also calculated that the risk of VT was increased by exposure to more flights during a short period and to longer flights and was greatest in the first two weeks after a flight. In addition, the risk of VT was particularly high in young employees, women taking oral contraceptives, and people who were short, tall or overweight.
What Do These Findings Mean?
The main finding of this study is that the absolute risk of VT after of a long-haul flight is low—only one passenger out of nearly 5,000 is likely to develop VT because of flying. However, the study included only healthy people without previous VT whose average age was 40 years, so the absolute risk of VT after long-haul flights might be higher in the general traveling population. Even so, this finding strongly suggests that prophylactic (preventative) use of anticoagulants by all long-haul travelers may not be justified because these drugs have potentially dangerous side effects (for example, they can cause uncontrolled bleeding). Subgroups of travelers with additional risk factors for VT might, however, benefit from the use of this and other prophylactic measures, but randomized trials are needed to find out who would benefit most from which prophylactic measure.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
Information from the US National Heart Lung and Blood Institute on deep vein thrombosis, including an animation of how DVT causes pulmonary embolisms
Information for patients from the UK National Health Service Direct health encyclopedia on deep vein thrombosis (in several languages)
Information for travelers on DVT from the US Centers for Disease Control and Prevention and from the UK National Travel Health Network and Centre
This study came out of the WHO Research Into Global Hazards of Travel (WRIGHT) project, and WHO's WRIGHT project on Air Travel and Venous Thromboembolism, of which his study forms a part, has a Web site
PMCID: PMC1989755  PMID: 17896862
25.  Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period 
Venous thromboembolic disease (TED), although rare, is a major cause of maternal mortality and morbidity, hence methods of prophylaxis are often used for women at risk. This may include women delivered by caesarean section, those with a personal or family history of TED and women with inherited or acquired thrombophilias (conditions that predispose people to thrombosis). Many methods of prophylaxis carry a risk of side effects, and as the risk of TED is low, it is possible that the benefits of thromboprophylaxis may be outweighed by harm. Current guidelines for clinical practice are based on expert opinion only, rather than high quality evidence from randomised trials.
To determine the effects of thromboprophylaxis in women who are pregnant or have recently delivered and are at increased risk of TED on the incidence of venous TED and side effects of treatment.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (May 2009).
Selection criteria
Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, and randomised trials comparing two (or more) methods of thromboprophylaxis.
Data collection and analysis
Two review authors extracted data independently and resolved any discrepancies by discussion.
Main results
Sixteen trials met the inclusion criteria but only 13 trials, involving 1774 women, examining a range of methods of thromboprophylaxis, contributed data for the outcomes of interest. Four of them compared methods of antenatal prophylaxis: low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) (two studies), and heparin versus no treatment (two studies). Eight studies assessed postnatal prophylaxis after caesarean section; one compared hydroxyethyl starch with unfractionated heparin; four compared heparin with placebo; and the other three compared UFH with LMWH. One study examined prophylaxis in the postnatal period.
The small number of statistically significant findings in this review are largely derived from trials which are not of high methodological quality. It was not possible to assess the effects of any of these interventions on most outcomes, and especially on rare outcomes such as death, TED and osteoporosis, because of small sample sizes and the small number of trials making the same comparisons.There was some evidence of side effects associated with thromboprophylaxis.
Authors’ conclusions
There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period. Large scale randomised trials of currently-used interventions should be conducted.
PMCID: PMC4175551  PMID: 20464719
Postpartum Period; Pregnancy Complications, Hematologic [* prevention & control]; Randomized Controlled Trials as Topic; Venous Thrombosis [* prevention & control]; Female; Humans; Pregnancy

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