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1.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 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.
Background
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 We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.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 Investigators were contacted for unpublished information about venous thromboembolic events during follow-up.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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001310.
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)
doi:10.1371/journal.pmed.1001310
PMCID: PMC3445446  PMID: 23028261
2.  Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide, Population-Based Case-Control Study 
PLoS ONE  2014;9(10):e110506.
Background
An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls.
Methods
We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden.
Results
1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89–1.02), nor for any risk category, OR 0.97 (95% CI 0.84–1.12) for low-risk disease, and OR 1.04 (95% CI 0.90–1.22) for metastatic disease.
Conclusion
The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.
doi:10.1371/journal.pone.0110506
PMCID: PMC4206421  PMID: 25337702
3.  Immediate Risk for Cardiovascular Events and Suicide Following a Prostate Cancer Diagnosis: Prospective Cohort Study 
PLoS Medicine  2009;6(12):e1000197.
Katja Fall and Fang Fang and colleagues find that men newly diagnosed with prostate cancer are at increased risk of cardiovascular events and suicide.
Background
Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.
Methods and Findings
We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4–12.1) during the first week and 1.9 (95% CI 1.9–2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5–3.2) during the first week and 1.3 (95% CI 1.3–1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9–22.7) during the first week and 2.6 (95% CI 2.1–3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.
Conclusions
Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Prostate cancer—a type of tumor that develops in a walnut-sized structure in the male reproductive system—is the commonest cancer (excluding skin cancer) among men in developed countries. In the USA and the UK, for example, one in six men will develop prostate cancer during their lifetime. Most prostate cancers develop in elderly men and, because these tumors usually grow relatively slowly, many men die with prostate cancer rather than as a result of it. Nevertheless, some prostate cancers are fast-growing and aggressive and prostate cancer is the second leading cause of cancer-related death among men. The symptoms of prostate cancer include problems urinating and excessive urination during the night. Nowadays, however, most prostate cancers are detected before they produce any symptoms by measuring the amount of a protein called the prostate-specific antigen (PSA) in the blood.
Why Was This Study Done?
Widespread PSA screening was introduced 20 years ago in the hope that early detection of prostate cancer would save lives. But, although many more prostate cancers are detected nowadays, the number of prostate cancer deaths has not changed significantly. Experts are divided, therefore, about whether the potential benefits of PSA screening outweigh its risks. Treatments for prostate cancer (for example, surgical removal of the prostate) may be more effective if they are started early but they can cause impotence and urinary incontinence, so should men be treated whose cancer might otherwise never affect their health? In addition, receiving a diagnosis of prostate cancer is stressful and there is growing evidence that stressful life events can increase an individual's risk of becoming ill or dying from a heart attack, stroke, or other “cardiovascular” events and of becoming mentally ill. In this study, therefore, the researchers investigate whether men diagnosed with prostate cancer in Sweden have increased risks of cardiovascular events and suicide during the first week and first year after their diagnosis.
What Did the Researchers Do and Find?
The researchers identified nearly 170, 000 men diagnosed with prostate cancer between 1961 and 2004 among Swedish men aged 30 years or older by searching the Swedish Cancer Register. They obtained information on subsequent fatal and nonfatal cardiovascular events and suicides from the Causes of Death Register and the Inpatient Register (in Sweden, everyone has a unique national registration number that facilitates searches of different health-related Registers). Before 1987, men with prostate cancer were about 11 times as likely to have a fatal cardiovascular event during the first week after their diagnosis as men without prostate cancer; during the first year after their diagnosis, men with prostate cancer were nearly twice as likely to have a cardiovascular event as men without prostate cancer (a relative risk of 1.9). From 1987, the relative risk of combined fatal and nonfatal cardiovascular events associated with a diagnosis of prostate cancer was 2.8 during the first week and 1.3 during the first year after diagnosis. The relative risk of suicide associated with a diagnosis of prostate cancer was 8.4 during the first week and 2.6 during the first year after diagnosis throughout the study period. Finally, men younger than 54 years at diagnosis had higher relative risks of both cardiovascular events and suicide.
What Do These Findings Mean?
These findings suggest that men newly diagnosed with prostate cancer have an increased risk of cardiovascular events and suicide. Because there is no information on tumor size or aggressiveness in the Cancer Register, the researchers could not look at the relationship between disease severity and the likelihood of a cardiovascular event or suicide. Furthermore, because of the study design, men who received a diagnosis of prostate cancer may have had additional characteristics in common that contributed to their increased risk of cardiovascular events and suicide. Nevertheless, these findings strongly suggest that the stress of the diagnosis itself rather than any subsequent treatment has deleterious effects on the health of men receiving a diagnosis of prostate cancer. Thus, strategies should be developed to reduce the risks of cardiovascular events and suicide—increased clinical and psychological monitoring—after a diagnosis of prostate cancer, particularly among young men, and this new information should be considered in the ongoing debate about the risks and benefits of PSA screening.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000197.
The US National Cancer Institute provides information on all aspects of prostate cancer, (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on prostate cancer, including Prostate Cancer Screening, A Decision Guide (some information in multiple languages)
The UK National Health Service Choices Web site provides detailed information on prostate cancer
The UK-based Samaritans charity provides confidential nonjudgmental emotional support, 24 hours a day, for people who are experiencing feelings of distress or despair, including those which could lead to suicide
Outside the UK, Befrienders provides information on help lines for those experiencing distress
doi:10.1371/journal.pmed.1000197
PMCID: PMC2784954  PMID: 20016838
4.  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.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1000098.
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
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
5.  Risk of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(7):e1001275.
Venous thromboembolism in patients with cancer is common, but precise incidence rates in different cancers are not known, making it difficult to target prevention strategies. This study summarizes the existing literature to determine the risk of venous thromboembolism in high- and average-risk groups of patients with different cancers.
Background
People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.
Methods and Findings
We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.
Conclusions
VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
A venous thrombosis is the medical term for a blood clot that forms in a vein, often completely blocking the vessel. The most common type is a deep vein thrombosis of the lower leg, which apart from causing pain and immobility, can break off (embolize), flow through the blood stream back to the heart, get caught in one of the blood vessels supplying the lungs, and cause a life-threatening pulmonary embolism. The term venous thromboembolism (VTE) refers to both a deep venous thrombosis and a pulmonary embolism and is a common cause of death, responsible for at least 300,000 deaths a year in the United States alone. There are many risk factors for developing a VTE, including age, immobility, certain medications, and some conditions, such as cancer: an estimated 20% of deaths from VTE occur among patients with cancer, and importantly, cancer patients with VTE have a much higher risk of death than those who do not have a VTE. The increased risk of developing a VTE is due to the treatments and surgery involved in the management of cancer, in addition to the risks associated with the condition itself.
Why Was This Study Done?
Previous studies have suggested that certain types of cancer, such as brain and pancreatic cancer, are associated with an increased risk of developing a VTE, but to date, clinical guidelines recommend preventative treatment of VTE only for cancer patients during hospital admissions for medical treatment and surgery, not for those patients receiving outpatient care. In this study, the researchers systematically reviewed the available published evidence to quantify the risks of developing a VTE in patients with cancer according to the type of cancer, and to determine whether certain patient groups are at particularly high risk of developing a VTE.
What Did the Researchers Do and Find?
The researchers used a comprehensive keyword search of two medical literature databases to identify relevant studies published between 1966 and 2011. Then they examined these studies according to certain criteria, such as the type of study and the type of cancer: the researchers were specifically looking for cohort studies of adult patients with one of eight cancer types—breast, lung, colorectal, prostate, brain, bone, pancreatic, and hematologic (including all leukemias, lymphomas, and multiple myeloma). The selected studies also had to include follow-up of more than 30 days and VTE outcomes. Then the researchers categorized selected studies according to the risk of developing a VTE—the researchers judged high-risk patients to be those with metastatic disease or receiving certain types of high-risk treatments, and judged average-risk patients to be representative of all patients with a cancer diagnosis. The researchers then pooled all the data from these studies and did a separate statistical analysis for high and average risk and for each cancer type.
Using these methods, the researchers identified 7,274 potentially relevant articles, of which 46 reports from 38 individual cohorts met the criteria to be included in their review. Of the 38 cohorts, the researchers categorized 31 as high risk and seven as average risk. In the pooled analysis the researchers found that among average-risk patients, the overall risk of VTE was 13 per 1,000 person-years, with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk, the researchers found that the risk of VTE was 68 per 1,000 person-years, with the highest risk among patients with brain cancer (200 per 1,000 person-years).
What Do These Findings Mean?
These findings suggest that the annual incidence rate of VTE in patients with cancer is between 0.5% and 20%, depending on the cancer type, background risk, and time since diagnosis. Cancers of the brain and pancreas have the highest risk of VTE for both high- and average-risk patient groups. Based on these more accurate data on the risks of VTE in different groups of cancer patients, future updates of clinical guidelines can now include more information about categories of risk to help guide clinicians when they make decisions about which patients should receive preventative treatment for VTE and when they should receive such treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10. 1371/journal.pmed.1001275.
Wikipedia gives more information about VTE (note that Wikipedia is a free online encyclopedia that anyone can edit)
Information about VTE for patients and health professionals is available from the American Cancer Society, the US National Cancer Institute, and the UK-based thrombosis charity Lifeblood
doi:10.1371/journal.pmed.1001275
PMCID: PMC3409130  PMID: 22859911
6.  Thromboembolic risks of recombinant factor VIIa Use in warfarin-associated intracranial hemorrhage: a case–control study 
BMC Neurology  2012;12:158.
Background
Recombinant factor VIIa (rFVIIa) may be used for rapid hemostasis in life-threatening hemorrhage. In warfarin-associated intracerebral hemorrhage (wICH), FVIIa use is controversial and may carry significant thromboembolic risks. We compared incidence of baseline thromboembolic risk factors and thromboembolism rates in wICH patients treated with additional rFVIIa to those treated with standard therapy of fresh frozen plasma (FFP) and vitamin K alone.
Methods
We identified 45 consecutive wICH patients treated with additional rFVIIa over 5-year period, and 34 consecutive wICH patients treated with standard therapy alone as comparison group. We compared the incidence of post-hemorrhage cardiac and extra-cardiac thromboembolic complications between two treatment groups, and used logistic regression to adjust for significant confounders such as baseline thromboembolic risk factors. We performed secondary analysis comparing the quantity of FFP transfused between two treatment cohorts.
Results
Both rFVIIa-treated and standard therapy-treated wICH patients had a high prevalence of pre-existing thromboembolic diseases including atrial fibrillation (73% vs 68%), deep venous thrombosis (DVT) or pulmonary embolism (PE) (22% vs 18%), coronary artery disease (CAD) (38% vs 32%), and abnormal electrocardiogram (EKG) (78% vs 85%). Troponin elevation following wICH was prevalent in both groups (47% vs 41%). Clinically significant myocardial infarction (MI), defined as troponin > 1.0 ng/dL, occurred in 13% of rFVIIa-treated and 6% of standard therapy-treated patients (p=0.52). Past history of CAD (p=0.0061) and baseline abnormal EKG (p=0.02) were independently associated with clinically significant MI following wICH while rFVIIa use was not. The incidences of DVT/PE (2% vs 9%; p=0.18) and ischemic stroke (2% vs 0%; p=0.38) were similar between two treatment groups. Recombinant FVIIa-treated patients had lower mean INR at 3 (p=0.0001) and 6 hours (p<0.0001) and received fewer units of FFP transfusion (3 vs 5; p=0.003).
Conclusions
Pre-existing thromboembolic risk factors as well as post-hemorrhage troponin elevation are prevalent in wICH patients. Clinically significant MI occurs in up to 13% of wICH patients. rFVIIa use was not associated with increased incidence of clinically significant MI or other venous or arterial thromboembolic events in this wICH cohort.
doi:10.1186/1471-2377-12-158
PMCID: PMC3538560  PMID: 23241423
Activated recombinant factor VII; Intracerebral hemorrhage; Thromboembolism; Warfarin
7.  Androgen Deprivation and Thromboembolic Events in Men with Prostate Cancer 
Cancer  2011;118(13):3397-3406.
Background
Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. Our objective was to estimate the impact of ADT on thromboembolic events (TEs) in a population-based cohort.
Methods
In the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified men aged over 65 diagnosed with non-metastatic prostate cancer between 1999 and 2005. Medical or surgical ADT was identified by Medicare claims for gonadotropin-releasing hormone agonists or bilateral orchiectomy at any time following diagnosis. TEs included deep venous thrombosis, pulmonary embolism, and arterial embolism. We estimated ADT’s impact on the risk of any TE and on total number of events, controlling for patient and tumor characteristics.
Results
Of 154,611 prostate cancer patients, 58,466 (38%) received ADT. During a median follow-up of 52 months, 15,950 men had at least one TE, including 8,829 (55%) who had ADT and 7,121 (45%) with no ADT. ADT was associated with increased risk of a TE (adjusted hazard ratio 1.56, 95% CI: 1.50 to 1.61, P < 0.0001), and duration of ADT was associated with the total number of events (P < 0.0001).
Conclusion
In this population-based cohort, ADT was associated with increased risk of a TE, and longer durations of ADT were associated with more TEs. Men with intermediate- and low-risk prostate cancer should be assessed for TE risk factors before starting ADT and counseled regarding the risks and benefits of this therapy.
doi:10.1002/cncr.26623
PMCID: PMC3678973  PMID: 22072494
prostate cancer; deep vein thrombosis; pulmonary embolism; androgen deprivation; arterial embolism
8.  Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism 
European urology  2012;61(6):1119-1128.
Background
Previous studies demonstrate that androgen deprivation therapy with gonodotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system.
Objective
To study the risk of peripheral arterial disease and venous thromboembolism associated with androgen deprivation therapy for prostate cancer.
Design, Settings and Participants
Population-based observational study of 182,757 U.S. men aged 66 years and older who were diagnosed with loco-regional prostate cancer from 1992 to 2007, of whom 47.8% received GnRH agonists and 2.2% orchiectomy.
Measurements
We used Cox proportional hazards models with time-varying treatment variables to assess whether treatment with GnRH agonists or orchiectomy was associated with peripheral arterial disease and/or venous thromboembolism.
Results and limitations
Overall, 47.8% of men received a GnRH agonist during follow-up and 2.2% underwent orchiectomy. GnRH agonist use was associated with an increased risk of incident peripheral arterial disease (adjusted hazard ratio [HR], 1.15, 95% confidence interval [CI] 1.11–1.19) and incident venous thromboembolism (adjusted HR, 1.1, 95% CI 1.04–1.16). In addition, orchiectomy was associated with an increased risk of peripheral arterial disease (adjusted HR, 1.14, 95% CI 1.03–1.27) and venous thromboembolism (adjusted HR, 1.22, 95% CI 1.07–1.40). Limitations include the observational study design, inability to assess the use of oral anti-androgens as monotherapy or combined androgen deprivation.
Conclusions
Androgen deprivation therapy for loco-regional prostate cancer is associated with an increased risk of peripheral artery disease and venous thromboembolism. Additional research is needed to better understand the potential risks and benefits, so that these treatments can be targeted to patients where the benefits are most clear.
doi:10.1016/j.eururo.2012.01.045
PMCID: PMC3719131  PMID: 22336376
Prostate cancer; androgen deprivation therapy; peripheral vascular disease; venous thromboembolism
9.  XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis 
Thrombosis Journal  2014;12:16.
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism, poses a substantial clinical risk, and the incidence of these thrombotic-related diseases remains high. Anticoagulation aims to prevent thrombus extension and reduce the risk of recurrent events, particularly fatal pulmonary embolism. In EINSTEIN DVT, rivaroxaban was non-inferior to enoxaparin/vitamin K antagonists for the reduction of recurrent VTE, with a similar safety profile and a net clinical benefit. EINSTEIN EXT investigated patients receiving long-term treatment in whom there was no clear decision about continuing or stopping anticoagulation; rivaroxaban was superior to placebo in the reduction of recurrent VTE, showing an acceptable benefit–risk balance. Rivaroxaban has the potential to replace standard therapy, usually parenteral low molecular weight heparin overlapping with and followed by a vitamin K antagonist, for the treatment of acute symptomatic DVT and the secondary prevention of VTE. As the use of rivaroxaban for DVT treatment increases in clinical practice, a fundamental understanding of its clinical benefits in everyday patient care is essential. XALIA (XArelto for Long-term and Initial Anticoagulation in venous thromboembolism) is a multicentre, prospective, non-interventional, observational study investigating the effectiveness and safety of a single-drug approach with rivaroxaban compared with standard therapy in patients with DVT. The study cohort will include approximately 4800 patients (≥18 years old) with objectively confirmed acute DVT who will be treated for a period of ≥3 months. The primary outcomes will be the incidence of treatment-emergent adverse events (primarily major bleeding), symptomatic recurrent venous thromboembolic events and all-cause mortality. Secondary outcomes include: major cardiovascular events; patient-reported treatment satisfaction and adherence; healthcare resource utilization; reasons for drug switching or interruption of treatment; and adverse events. XALIA will follow an international cohort of patients in more than 20 European countries, and others including Israel and Canada. The first patient was enrolled in June 2012, with results expected in 2015. It is anticipated that XALIA will provide important information on the treatment of DVT in a heterogeneous, unselected patient population in a real-world setting and provide important supplementary information to that obtained from the EINSTEIN DVT phase III study.
doi:10.1186/1477-9560-12-16
PMCID: PMC4120724  PMID: 25093014
Deep vein thrombosis; Outcomes; Real-world experience; Rivaroxaban
10.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows 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 clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
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
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
11.  Population-based study on use of chemotherapy in men with castration resistant prostate cancer 
Acta Oncologica (Stockholm, Sweden)  2013;52(8):1593-1601.
Background.
Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC.
Material and methods.
To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that men who died of prostate cancer (PCa) underwent a period of CRPC before they died.
Results.
Among the 2677 men who died from PCa during the study inclusion period, 556 (21%) had received chemotherapy (intravenous or per oral) detectable within the observation period in SALT database. Specifically, 239 (61%) of men < 70 years had received chemotherapy, 246 (30%) of men between 70 and 79 years and 71 (5%) men older than 80 years. The majority of men 465/556 (84%) had received a docetaxel-containing regimen. Among chemotherapy treated men, 283/556 (51%) received their last dose of chemotherapy during the last six months prior to death. Treatment with chemotherapy was more common among men with little comorbidity and high educational level, as well as in men who had received curatively intended primary treatment.
Conclusion.
A majority of men younger than 70 years with CRPC were treated with chemotherapy in contrast to men between 70 and 79 years of whom half as many received chemotherapy. Chemotherapy treatment was often administered shortly prior to death. The low uptake of chemotherapy in older men with CRPC may be caused by concerns about tolerability of treatment, as well as treatment decisions based on chronological age rather than global health status.
doi:10.3109/0284186X.2013.770164
PMCID: PMC3812701  PMID: 23427879
12.  Cardiac and Thromboembolic Complications and Mortality in Patients Undergoing Total Hip and Total Knee Arthroplasty 
Annals of the Rheumatic Diseases  2011;70(12):2082-2088.
Objective
Study 90-day cardiac and thromboembolic complications and all-cause mortality following total hip or knee arthroplasty (THA/TKA).
Method
In a population-based cohort of all Olmsted County residents who underwent a THA or TKA between 1994 and 2008, we assessed 90-day occurrence and predictors of cardiac complications (myocardial infarction, cardiac arrhythmia or congestive heart failure), thromboembolic complications (deep venous thrombosis (DVT) or pulmonary embolism (PE)) and mortality.
Results
Among the Olmsted County THA and TKA cohorts, 90-day complication rates were as follows: cardiac, 15.8% and 6.9%; thromboembolic, 4.9% and 4.0%; and mortality, 0.7% and 0.4%, respectively. Unadjusted frequency of cardiac/thromboembolic events differed by history of prior respective event. In multivariable-adjusted logistic regression analyses, ASA class III–IV (OR, 6.1, 95% CI:1.6, 22.8) and higher Deyo-Charlson comorbidity score (OR, 1.2, 95% CI:1.0,1.4) were significantly associated with odds of 90-day cardiac event post-THA in patients with no known prior cardiac event. In those with known prior cardiac disease, ASA class III–IV (OR, 4.4, 95% CI:2.0, 9.9), male gender (OR, 0.5, 95% CI:0.3,0.9) and history of thromboembolic disease (OR, 3.2; 95% CI:1.4,7.0) were significantly associated with odds of cardiac complication 90-day post-THA. No significant predictors of thromboembolism were found in THA patients.
In TKA patients with no prior cardiac history, age >65 years (OR, 4.1, 95% CI:1.2, 14.0), and ASA class III–IV (OR, 2.8, 95% CI:1.1,6.8) and in TKA patients with known cardiac disease, ASA class III–IV (OR, 3.2, 95% CI:1.8,5.7) was significantly associated with odds of 90-day cardiac event. In TKA patients with no prior thromboembolic disease, male gender (OR, 0.5, 95% CI:0.2,0.9) and higher Charlson index (OR, 1.2, 95% CI:1.1,1.3) and in patients with known thromboembolic disease, higher Charlson index score (OR, 1.1, 95% CI:1.1,1.4) was associated with odds of 90-day thromboembolic event.
Conclusion
Older age, higher comorbidity, higher ASA class and prior history of cardiac/thromboembolic disease was associated with an increased risk of 90-day cardiac and thromboembolic complications.
doi:10.1136/ard.2010.148726
PMCID: PMC3315837  PMID: 22021865
Cardiac; Thromboembolic; Total Hip Arthroplasty; Total Knee Arthroplasty; Mortality
13.  Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study 
Objectives To derive and validate a new clinical risk prediction algorithm (QThrombosis, www.qthrombosis.org) to estimate individual patients’ risk of venous thromboembolism.
Design Prospective open cohort study using routinely collected data from general practices. Cox proportional hazards models used in derivation cohort to derive risk equations evaluated at 1 and 5 years. Measures of calibration and discrimination undertaken in validation cohort.
Setting 564 general practices in England and Wales contributing to the QResearch database.
Participants Patients aged 25-84 years, with no record of pregnancy in the preceding 12 months or any previous venous thromboembolism, and not prescribed oral anticoagulation at baseline: 2 314 701 in derivation cohort and 1 240 602 in validation cohort.
Outcomes Incident cases of venous thromboembolism, either deep vein thrombosis or pulmonary embolism, recorded in primary care records or linked cause of death records.
Results The derivation cohort included 14 756 incident cases of venous thromboembolism from 10 095 199 person years of observation (rate of 14.6 per 10 000 person years). The validation cohort included 6913 incident cases from 4 632 694 person years of observation (14.9 per 10 000 person years). Independent predictors included in the final model for men and women were age, body mass index, smoking status, varicose veins, congestive cardiac failure, chronic renal disease, cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, hospital admission in past six months, and current prescriptions for antipsychotic drugs. We also included oral contraceptives, tamoxifen, and hormone replacement therapy in the final model for women. The risk prediction equation explained 33% of the variation in women and 34% in men in the validation cohort evaluated at 5 years The D statistic was 1.43 for women and 1.45 for men. The receiver operating curve statistic was 0.75 for both sexes. The model was well calibrated.
Conclusions We have developed and validated a new risk prediction model that quantifies absolute risk of thrombosis at 1 and 5 years. It can help identify patients at high risk of venous thromboembolism for prevention. The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records. The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism.
doi:10.1136/bmj.d4656
PMCID: PMC3156826  PMID: 21846713
14.  Symptomatic and Incidental Venous Thromboembolic Disease Are Both Associated with Mortality in Patients with Prostate Cancer 
PLoS ONE  2014;9(8):e94048.
Introduction
The association between malignancy and venous thromboembolic disease (VTE) is well established. The independent impact of VTE, both symptomatic and incidental, on survival in patients with prostate cancer is not known. We conducted a retrospective cohort study to evaluate the effect of VTE of survival in prostate cancer.
Methods
Data regarding clinical characteristics, treatment and outcomes of 453 consecutive prostate cancer patients were collected. Fisher exact (categorical variables) and t-test (continuous variables) were utilized to test associations with VTE and mortality. Survival was estimated using the Kaplan Meier method. A Cox regression model was used to model the mortality hazard ratio (HR).
Results
At diagnosis, 358 (83%) patients had early stage disease, 43 (10%) had locally advanced disease and 32 (7%) had metastatic disease. During the follow up period, 122 (27%) patients died and 41 (9%) developed VTE (33 deep vein thrombosis, 5 pulmonary embolism, and 3 patients with both DVT and PE). Twenty-five VTE events were symptomatic and 16 were incidentally diagnosed on CT scans obtained for other reasons. VTE was associated with increased mortality [HR 6.89 (4.29–11.08), p<0.001] in a multivariable analysis adjusted for cancer stage, performance status, treatments and co-morbidities. There was no difference in survival between patients who had symptomatic and incidental VTE.
Conclusion
Venous thromboembolic disease, both symptomatic and incidental, is a predictor of poor survival in patients with prostate cancer, especially those with advanced disease. Further studies are needed to evaluate the benefit of prophylactic and therapeutic anticoagulation in this population.
doi:10.1371/journal.pone.0094048
PMCID: PMC4134135  PMID: 25126949
15.  Thromboembolism 
Clinical Evidence  2011;2011:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low molecular weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT compared with placebo or no treatment.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin. Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC3217723  PMID: 21385473
16.  Thromboembolism 
Clinical Evidence  2010;2010:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low-molecular-weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin.Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC2907619
17.  Thromboembolic Complications Following Spine Surgery Assessed with Spiral CT Scans 
HSS Journal  2010;7(1):37-40.
Spine surgery is associated with a significant risk of postoperative pulmonary embolism (PE) and/or deep vein thrombosis (DVT). The goal of this study was to determine which symptoms and risk factors were associated with spiral CT scans positive for PE and/or DVT in the postoperative spine surgery patient. We conducted a retrospective review of all spine patients who underwent a postoperative CT to rule out PE during the period of March 2004–February 2006. The type of surgical procedure, risk factors, symptoms prompting scan ordering, anticoagulation, and treatment were recorded. Logistic regression models were used to determine significant predictors of a positive CT in this patient population. Of the 3,331 patients that had spine surgery during the study period, 130 (3.9%) had a spiral CT scan to rule out PE and/or proximal DVT. Thirty-three of the 130 (25.4%) CT scans were positive for PE only, five (3.8%) for PE and DVT, and three (2.3%) for DVT only. Only 24.5% (32) patients had risk factors for thromboembolic disease, and of these, a history of PE and/or DVT was the only significant risk factor for a positive scan (p = 0.03). No presenting symptoms or demographic variables were noted to have a significant association with PE and/or DVT. The type of surgical procedure (i.e., anterior, posterior, and percutaneous) was not associated with an increased risk for PE and/or DVT. Patients who are undergoing spine surgery with a history of thromboembolic disease should be carefully monitored postoperatively and may benefit from more aggressive prophylaxis.
doi:10.1007/s11420-010-9179-7
PMCID: PMC3026105  PMID: 22294955
spine surgery; spiral CT; thromboembolism
18.  A Randomized Trial of Rosuvastatin in the Prevention of Venous Thromboembolism: the JUPITER Trial 
The New England journal of medicine  2009;360(18):1851-1861.
Background
Controversies persist on whether arterial and venous thrombosis share common pathways and whether treatments of known efficacy for one disease process have consistent benefits for the other. Observational studies have yielded variable estimates of the effect of statin therapy on risk of venous thromboembolism, and randomized evidence is lacking.
Methods
Symptomatic venous thromboembolism was a pre-specified endpoint of Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg/dL and high-sensitivity C-reactive protein levels of 2.0 mg/L or higher to rosuvastatin, 20 mg/d, or placebo. Intention-to-treat analyses followed participants for the first occurrence of pulmonary embolism or deep vein thrombosis.
Results
During a median follow-up of 1.9 years (maximum 5.0), symptomatic venous thromboembolism occurred in 94 participants, 34 in the rosuvastatin group and 60 in the placebo group. The rates of venous thromboembolism were 0.18 and 0.32 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin 0.57; 95% confidence interval [CI], 0.37 to 0.86; P=0.007), with corresponding rates of 0.10 and 0.17 for unprovoked venous thromboembolism (hazard ratio 0.61; 95% CI, 0.35 to 1.09; P=0.089) and 0.08 and 0.16 for provoked venous thromboembolism (hazard ratio 0.52; 95% CI, 0.28 to 0.96; P=0.033). Corresponding rates of pulmonary embolism were 0.09 and 0.12 (hazard ratio 0.77; 95% CI, 0.41 to 1.45; P=0.42), whereas rates of deep vein thrombosis only were 0.09 and 0.20 (hazard ratio 0.45; 95% CI, 0.25 to 0.79; P=0.004). Consistent effects were observed in all subgroups examined. No differences were seen between treatment groups in rates of bleeding.
Conclusions
In this trial of apparently healthy persons, rosuvastatin significantly reduced the occurrence of symptomatic venous thromboembolism. (ClinicalTrials.gov number, NCT00239681.)
doi:10.1056/NEJMoa0900241
PMCID: PMC2710995  PMID: 19329822
19.  Safety and efficacy of low-molecular-weight heparins in prophylaxis of deep vein thrombosis in postoperative/ICU patients: A comparative study 
Background:
Venous thromboembolism (VTE), although a very common problem in everyday clinical practice, remains asymptomatic in most cases. Clinical diagnosis helps identify those who are going to have thromboembolic episode. A combination of clinical scoring systems like Wells’ score and D-dimer assay provide a useful diagnostic tool. Trauma (surgical or accidental) and critically ill patients are found to have greatest risk. Enoxaparin and dalteparin are amongst the most common low-molecular-weight heparins (LMWHs) used for deep venous thrombosis (DVT) prophylaxis in such patients.
Aim:
The present study is designed to compare their role in preventing DVT in postoperative or critically ill patients and to determine their relative safety profiles.
Materials and Methods:
The study included 36 critically ill adult patients. All the patients were allocated into three groups of 12 patients each. Group I patients received no prophylaxis, group II received inj. enoxaparin s/c 0.6-0.8 mg/kg twice daily, and group III received inj. dalteparin s/c 125-250 units/kg once daily. Routine investigations and coagulation profile were recorded on admission to intensive care unit (ICU) and at every third day thereafter. Patients were daily assessed for pretest probability of DVT using Wells’ scoring, and D-dimer test was done on the 7th day. Occurrence of any bleeding (visible or occult) was noted, and incidence of DVT was determined in each group using positive results of D-dimer test and the clinical assessment with Wells’ score.
Results:
A significant difference in Wells’ score (P < 0.05) was found between groups I and III on day 5 and day 7. A lower, but insignificant difference in the incidence of DVT was found between the study and control groups. No significant difference in major bleeding or other side effects was found. Better hemodynamic status and arterial blood gases in the study groups may indirectly refer to absence of asymptomatic DVT or silent pulmonary embolism in this group.
Conclusion:
The present study suggests that LMWHs, namely, enoxaparin and dalteparin, provide effective means of preventing DVT in high-risk, critically ill or postoperative patients, without causing any significant increase in the risk of bleeding or other side effects. Dalteparin appears to be unaffected by low creatinine clearance as explained by its clearance by a non-saturable mechanism. Still, a more extensive study with larger population is needed to make the outcomes worthwhile.
doi:10.4103/0976-9668.107290
PMCID: PMC3633277  PMID: 23633862
D-dimer; deep vein thrombosis; low-molecular-weight heparin; venous thromboembolism
20.  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.
Background
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.
Conclusions
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
Background.
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 http://dx.doi.org/10.1371/journal.pmed.0040290.
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
doi:10.1371/journal.pmed.0040290
PMCID: PMC1989755  PMID: 17896862
21.  Patterns of Use and Risks Associated With Erythropoiesis-Stimulating Agents Among Medicare Patients With Cancer 
Background
Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist.
Methods
We identified patients who were aged 65 years or older in the Surveillance, Epidemiology, and End Results–Medicare database; who were diagnosed with colon, non–small cell lung, or breast cancer or with diffuse large B-cell lymphoma from January 1, 1991, through December 31, 2002; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (ie, deep vein thrombosis or pulmonary embolism), and overall survival. We used multivariable logistic regression models to analyze the association of erythropoiesis-stimulating agent use with clinical and demographic variables. We used time-dependent Cox proportional hazards models to analyze the association of time to receipt of first erythropoiesis-stimulating agent with venous thromboembolism and overall survival. All statistical tests were two-sided.
Results
Among 56 210 patients treated with chemotherapy from 1991 through 2002, 15 346 (27%) received an erythropoiesis-stimulating agent. The proportion of patients receiving erythropoiesis-stimulating agents increased from 4.8% in 1991 to 45.9% in 2002 (P < .001). Use was associated with more recent diagnosis, younger age, urban residence, comorbidities, receipt of radiation therapy, female sex, and metastatic or recurrent cancer. The rate of blood transfusion per year during 1991–2002 remained constant at 22%. Venous thromboembolism developed in 1796 (14.3%) of the 12 522 patients who received erythropoiesis-stimulating agent and 3400 (9.8%) of the 34 820 patients who did not (hazard ratio = 1.93, 95% confidence interval = 1.79 to 2.07). Overall survival was similar in both groups.
Conclusion
Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.
doi:10.1093/jnci/djp387
PMCID: PMC2786918  PMID: 19903808
22.  Mortality following Hip Fracture in Men with Prostate Cancer 
PLoS ONE  2013;8(9):e74492.
Background
Hip fractures are associated with increased mortality and are a known adverse effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). It was our aim to evaluate how mortality after hip fracture is modified by PCa and ADT.
Methods
PCa dataBase Sweden (PCBaSe 2.0) is based on the National PCa Register and also contains age and county-matched PCa-free men. We selected all men (n = 14,205) who had been hospitalized with a hip fracture between 2006 and 2010; 2,300 men had a prior PCa diagnosis of whom 1,518 (66%) were on ADT prior to date of fracture. Risk of death was estimated with cumulative incidence and standardized mortality ratios (SMRs) to make comparisons with the entire PCa population and the general population.
Results
Cumulative incidences indicated that there was a higher risk of death following a hip fracture for PCa men on ADT than for PCa men not on ADT or PCa-free men, particularly in the first year. The SMRs showed that PCa men on ADT with a hip fracture were 2.44 times more likely to die than the comparison cohort of all PCa men (95%CI: 2.29-2.60). This risk was especially increased during the first month (5.64 (95%CI: 4.16–7.48)). In absolute terms, hip fractures were associated with 20 additional deaths per 1,000 person-years in PCa men not on ADT, but 30 additional deaths per 1,000 person-years for PCa men on ADT, compared to all PCa men.
Conclusion
Hip fractures are associated with higher all-cause mortality in PCa men on ADT than in PCa men not on ADT or PCa-free men, especially within the first three months.
doi:10.1371/journal.pone.0074492
PMCID: PMC3785484  PMID: 24086350
23.  Variation in thromboembolic complications among patients undergoing commonly performed cancer operations 
Journal of Vascular Surgery  2012;55(4):1035-1040.e4.
Objective
There is widespread evidence that cancer confers an increased risk of deep venous thrombosis (DVT). This risk is thought to vary among different cancer types. The purpose of this study is to better define the incidence of thrombotic complications among patients undergoing surgical treatment for a spectrum of prevalent cancer diagnoses in contemporary practice.
Methods
All patients undergoing one of 11 cancer surgical operations (breast resection, hysterectomy, prostatectomy, colectomy, gastrectomy, lung resection, hepatectomy, pancreatectomy, cystectomy, esophagectomy, and nephrectomy) were identified by Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes using the American College of Surgeons National Surgical Quality Improvement Program database (2007–2009). The study endpoints were DVT, pulmonary embolism (PE), and overall postoperative venous thromboembolic events (VTE) within 1 month of the index procedure. Multivariate logistic regression was utilized to calculate adjusted odds ratios for each endpoint.
Results
Over the study interval, 43,808 of the selected cancer operations were performed. The incidence of DVT, PE, and total VTE within 1 month following surgery varied widely across a spectrum of cancer diagnoses, ranging from 0.19%, 0.12%, and 0.28% for breast resection to 6.1%, 2.4%, and 7.3%, respectively, for esophagectomy. Compared with breast cancer, the incidence of VTE ranged from a 1.31-fold increase in VTE associated with gastrectomy (95% confidence interval, 0.73–2.37; P = .4) to a 2.68-fold increase associated with hysterectomy (95% confidence interval, 1.43–5.01; P = .002). Multivariate logistic regression revealed that inpatient status, steroid use, advanced age (≥60 years), morbid obesity (body mass index ≥35), blood transfusion, reintubation, cardiac arrest, postoperative infectious complications, and prolonged hospitalization were independently associated with increased risk of VTE.
Conclusions
The incidence of VTE and thromboembolic complications associated with cancer surgery varies substantially. These findings suggest that both tumor type and resection magnitude may impact VTE risk. Accordingly, such data support diagnosis and procedural-specific guidelines for perioperative VTE prophylaxis and can be used to anticipate the risk of potentially preventable morbidity.
doi:10.1016/j.jvs.2011.10.129
PMCID: PMC3339376  PMID: 22409858
24.  Is thromboprophylaxis effective in reducing the pulmonary thromboembolism? 
ARYA Atherosclerosis  2012;8(1):16-20.
BACKGROUND
Deep vein thrombosis (DVT) is a relatively prevalent disease which causes high costs due to the required diagnostic tests, specialized treatments, and hospital admission. In recent decades, implementation of thromboprophylaxis protocols has significantly reduced the incidence of thromboembolism in hospitals. The present study aimed to compare the incidence of venous thromboembolism before and after implementation of the mentioned protocol in hospital with identified risk factors and underlying diseases.
METHODS
In this case-control group, 385 patients at the risk of DVT, some before and some after implementation of the protocol were studied. Therefore, the level of thromboprophylaxis and the incidence of venous thromboembolism were compared before and after the protocol. Data was entered into SPSS15 and analyzed by chi-square and t tests
RESULTS
Out of 385 patients, 34 patients (8.8%) had venous thromboembolism while 351 (91.2%) were not affected. The incidence of venous thromboembolism was significantly different before and after the implementation of the protocol (17.7% vs. 5.9%; P < 0.001). The incidence of venous thromboembolism in patients not receiving thromboprophylaxis was almost 5 times higher than those who received it (20.7% vs. 5.1%). The frequency distribution of thromboembolism had a significant difference in the two above mentioned groups (P < 0.001).
CONCLUSION
Thromboprophylaxis protocol reduced venous thromboembolism incidence in patients with underlying diseases which increase the risk of the complication.
PMCID: PMC3448396  PMID: 23056095
Deep vein thrombosis; Thromboprophylaxis
25.  Infection and Venous Thromboembolism in Patients Undergoing Colorectal Surgery: What Is the Relationship? 
Diseases of the colon and rectum  2014;57(4):497-505.
BACKGROUND
There is evidence demonstrating an association between infection and venous thromboembolism. We recently identified this association in the postoperative setting; however, the temporal relationship between infection and venous thromboembolism is not well defined
OBJECTIVE
We sought to determine the temporal relationship between venous thromboembolism and postoperative infectious complications in patients undergoing colorectal surgery.
DESIGN, SETTING, AND PATIENTS
A retrospective cohort analysis was performed using data for patients undergoing colorectal surgery in the National Surgical Quality Improvement Project 2010 database.
MAIN OUTCOME MEASURES
The primary outcome measures were the rate and timing of venous thromboembolism and postoperative infection among patients undergoing colorectal surgery during 30 postoperative days.
RESULTS
Of 39,831 patients who underwent colorectal surgery, the overall rate of venous thromboembolism was 2.4% (n = 948); 729 (1.8%) patients were diagnosed with deep vein thrombosis, and 307 (0.77%) patients were diagnosed with pulmonary embolism. Eighty-eight (0.22%) patients were reported as developing both deep vein thrombosis and pulmonary embolism. Following colorectal surgery, the development of a urinary tract infection, pneumonia, organ space surgical site infection, or deep surgical site infection was associated with a significantly increased risk for venous thromboembolism. The majority (52%–85%) of venous thromboembolisms in this population occurred the same day or a median of 3.5 to 8 days following the diagnosis of infection. The approximate relative risk for developing any venous thromboembolism increased each day following the development of each type of infection (range, 0.40%–1.0%) in comparison with patients not developing an infection.
LIMITATIONS
We are unable to account for differences in data collection, prophylaxis, and venous thromboembolism surveillance between hospitals in the database. Additionally, there is limited patient follow-up.
CONCLUSIONS
These findings of a temporal association between infection and venous thromboembolism suggest a potential early indicator for using certain postoperative infectious complications as clinical warning signs that a patient is more likely to develop venous thromboembolism. Further studies into best practices for prevention are warranted.
doi:10.1097/DCR.0000000000000054
PMCID: PMC4332793  PMID: 24608307
Colorectal surgery; Venous thromboembolism; Surgical site infection; Surgical outcome; National Surgical Quality Improvement Project

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