Citations

Abstract Active cancer is an independent VTE risk factor (overall 6- to 9-fold increased risk) and accounts for almost 20% of all VTE in the community, but which cancer patients are at risk for VTE is largely unknown. Reportedly, VTE risk varies by tumor site, and cancer of the ovary, pancreas, colon, stomach, lung, prostate, and kidney convey particularly high VTE risk. Objective: To estimate VTE risk by tumor site. Methods: We enumerated observed cancers by tumor site for Olmsted County, MN active cancer patients with incident VTE over the seven-year period, 1991–1997 (n=152). We used 1991–1997 State Surveillance, Epidemiology, and End Results (SEER) data for Iowa to estimate the expected age-specific prevalence of cancer by tumor site in Olmsted County. VTE risk ratios (RR) for each tumor site were estimated by dividing the observed number of cancers by the expected number (calculated as the product of the SEER prevalence and the number of incident VTE cases in the age stratum). Results: For our population of 1991–1997 VTE cases, all tumor sites had RR > 5.0 (range 5.2 to 37.3, all p-values<0.05). Compared to published overall VTE odds ratios of 6–9 for active cancer compared to no cancer, the RR for some tumor sites were particularly increased. A Chi-squared test of heterogeneity of the RR across sites was highly significant (p-value<0.001). Three rare cancer sites - pancreatic cancer, lymphoma, and brain cancer - had unusually high RR (all RR>25). The high number of VTE cases with lymphoma was not due to catheter-related arm vein thrombosis. Liver, leukemia, other gastrointestinal (esophagus, small intestine, gallbladder, other biliary) and other gynecologic (primarily cervical) cancers had over twice the baseline risk (i.e., RR>17.0). On the other hand, the RR for many common cancers (breast, colorectal, ovary, lung, prostate) were essentially the same as the overall baseline risk (all had 9.5<RR<12.0). Conclusions: In contrast to previous reports, pancreas, lymphoma, brain, liver, leukemia, other gastrointestinal, and other gynecologic cancers have the highest VTE risk. Prior estimates of VTE risk by tumor site may have been biased by studies of prevalent cancers among patients hospitalized in tertiary care centers.

Abstract If the incidence of VTE varies by season, then the etiology of VTE could be related to seasonal exposures. However, the few studies that estimated VTE incidence by season reached conflicting conclusions. Objective: To estimate the incidence of VTE by month and by season of the year. Methods: Using the resources of the Rochester Epidemiology Project, we identified the inception cohort of Olmsted County, MN, residents with a first lifetime VTE over the 30-year period, 1966–1995 (n=2761). For each case, we reviewed the complete medical records in the community for the date of VTE onset, date of birth, gender and 48 baseline clinical characteristics commonly accepted as risk factors for VTE. We categorized cases as idiopathic (n=305) if no such characteristics were present; remaining cases were categorized as secondary. Incidence rates were calculated using the number of overall, idiopathic or secondary VTE cases by month of onset as the numerator, and age- and sex-specific estimates of the monthly population of Olmsted County as the denominator (yearly population estimates divided by 12). Results: The incidence of VTE did not vary appreciably by month of the year for overall, idiopathic or secondary VTE (all p-values >0.2). However, the overall incidence of VTE was higher in the 3 summer months (June, July, August) compared to the 3 winter months (December, January, February; 132.6 vs. 116.9 per 100,000 person-years, respectively, both age- and sex-adjusted to year 2000 U.S. Whites; p-value = 0.026). The same general pattern was true for both idiopathic and secondary VTE, but separately neither was statistically significant (p-value=0.48 and 0.15, respectively). Conclusions: The incidence of VTE is higher in the summer compared to the winter months, suggesting the hypothesis that vector-borne (e.g., mosquito, tick) and/or enteroviral infection may play a role in the etiology of VTE.

Abstract Background IL-10 polarized macrophages promote tumor growth and survival. The T-cell transcription factor GATA binding protein-3 (GATA3) epigenetically regulates IL10 expression. Therefore, we investigated the extent to which GATA-3 regulates IL-10 production and macrophage polarization in T-cell lymphomas. Methods Monocyte-derived macrophages were generated and polarized with T-cell lymphoma conditioned media ((TCL-CM). Immunophenotypic and functional characteristics associated with IL10-polarized macrophages were examined. GATA3-dependent cytokine production was evaluated in T-cell lymphoma lines by shRNA knockdown. Alternatively polarized macrophages and GATA3 expression were examined in a cohort of patients with peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) (n=76). Comparisons among groups were evaluated using a Student's t test. Progression-free and overall survival (PFS & OS) was estimated using the Kaplan-Meier method and two-tailed log-rank test based on Cox proportional hazards model. Results To investigate the ability of T-cell lymphomas to alternatively polarize macrophages, monocytes from healthy donors were cocultured with TCL-CM. Macrophages were shown to have immunophenotypic characteristics of IL10-polarized macrophages (pSTAT3+/CD16hi/CD163hi/HLA-DR-/lo) by flow cytometry, which was abrogated by IL10, but not IL6, neutralization. TCL-CM polarized macrophages produced abundant IL-10 and were impaired in their ability to stimulate T-cell proliferation. Collectively, these results demonstrate that T-cell lymphomas promote alternative macrophage polarization in an IL-10 dependent manner, and both CD163 and pSTAT3 may aid in their identification in clinical T-cell lymphoma specimens. Therefore, CD163+/pSTAT3+ macrophages were visualized by immunofluorescence in PTCL, NOS specimens. IL-10 polarized macrophages were not identified in normal tissues, but were abundant constituents of the tumor microenvironment in 68% of the PTCL, NOS specimens examined (n=31). STAT3 phosphorylation in response to IL-10 is dependent upon the Janus kinases (JAK) JAK1 and TYK2, both of which are inhibited at nanomolar (and clinically achievable) concentrations by the “JAK2” inhibitor ruxolitinib. Therefore, we sought to determine whether ruxolitinib may prevent IL-10-induced macrophage polarization. As expected, ruxolitinib inhibited IL-10-induced STAT3 phosphorylation. More importantly, macrophages polarized in the presence of ruxolitinib lost the immunophenotype characteristics of IL-10 polarized macrophages, and were CD16-/loCD163-/loHLA-DRhi. Furthermore, IL-10 production was significantly impaired in macrophages polarized in the presence of ruxolitinib, while their ability to stimulate T-cell proliferation was significantly increased. In a separate initiative, we identified GATA3 as the key regulator of IL-10 and Th2 cytokine (IL-4, IL-13 and IL-5) expression in T-cell lymphoma lines by shRNA knockdown assays. Therefore, we examined GATA3 expression by immunohistochemistry in PTCL, NOS specimens. GATA-3 expression was observed in most of the T-cell lymphoma lines and in 47% of PTCL, NOS specimens (n=76). In the cohort of the 76 PTCL, NOS patients, the median PFS and OS observed in GATA3+ PTCL, NOS was 5 months (4-8 months, 95% CI) and 8 months (5-14 months, 95% CI), respectively. In contrast, the median PFS and OS in GATA3- PTCL, NOS was 1.3 years (0.6-1.6, 95% CI) and 1.6 years (0.7-6.9 95% CI), respectively. Conclusions Alternatively polarized macrophages are abundant in T-cell lymphomas and are generated in an IL-10- and STAT3-dependent manner. GATA-3 regulates IL-10 production in these lymphomas, and its expression identified a high-risk subset of PTCL, NOS with distinct clinicopathological features. As IL-10-dependent STAT3 phosphorylation and macrophage polarization were impaired by ruxolitinib, the JAK2 inhibitors may warrant closer scrutiny as immunomodulatory agents. Disclosures: Off Label Use: Ruxolitinib, a JAK2 inhibitor, may warrant closer scrutiny as an immunomodulatory agent in TCL therapeutics.

Abstract Background Recurrent VTE is frequent and may be fatal; the 2-week case fatality rate after recurrent pulmonary embolism is 11%. However, predictors of VTE recurrence remain uncertain. Objective To identify independent predictors of VTE recurrence, including interim exposures, adjusted for baseline characteristics and treatments. Methods Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988-2000. All patients surviving ≥1 day were followed forward in time for first objectively-diagnosed VTE recurrence, death or other loss to follow-up, or 12/31/2005, whichever came first. VTE recurrence was defined as new thrombosis of a previously uninvolved venous territory or re-thrombosis of a previously involved venous territory after interim clearing of the incident thrombosis. We estimated the cumulative incidence of VTE recurrence using the Kaplan Meier product limit method, both overall and by incident cancer-associated, idiopathic and non-cancer secondary VTE. For all patients with VTE recurrence, and a random sample of all patients with incident VTE, we reviewed the complete medical records in the community and collected demographic and baseline characteristics, treatments (heparin and warfarin [including proportion of time in therapeutic range], IVC filter, aspirin, statins) and interim VTE risk factor exposures. Using a case-cohort study design with Barlow’s weighting scheme, we tested these demographic, baseline and interim characteristics as potential predictors of VTE recurrence using time-dependent Cox proportional hazards modeling. Results Among 1261 incident VTE patients who survived ≥1 day, 306 developed recurrent VTE over 6,485 person-years of follow-up. The cumulative incidence of VTE recurrence at 30 and 180 days, and 1 and 5 years, were 4.5%, 8.2%, 10.5% and 20.3%, respectively. The five-year cumulative recurrence rates among patients with incident cancer-associated, idiopathic and non-cancer secondary VTE were 42.6%, 26.8% and 18.5%, respectively. Among the random cohort of 415 incident VTE cases, 381 (92%) and 359 (87%) received heparin and warfarin therapy for a median (IQR) 5 (4 - 7) and 119 (63 - 194) days, respectively. From multivariable analysis, interim exposure to trauma, major surgery (general, cardiac or gynecologic), infection, hospitalization for acute medical illness or active cancer after the incident VTE were each associated with an increased hazard of VTE recurrence, while use of warfarin and achievement of a therapeutic APTT within the first day of starting heparin were associated with reduced hazards. Although measures of time in therapeutic range while on heparin or warfarin were associated with a reduced risk of recurrence from univariate analyses, these results were not significant when adjusting for other risk factors. Conclusions Among patients with incident VTE, new exposure to trauma, major surgery, infection, hospitalization for acute medical illness or active cancer are independent predictors of VTE recurrence; patients with such exposures should be considered for VTE prophylaxis. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 476 Background: The burden of VTE among nursing home (NH) residents is known to be high. Yet very little data exist to help determine which NH residents to target for VTE prophylaxis. The need to characterize VTE risk in this population is especially great because the advanced age and high comorbidity that typify NH residents contribute to increased likelihood of adverse consequences from VTE prophylaxis. To compound the problem, results of our prior univariate analyses of certain factors known to contribute substantially to VTE risk in the general population (e.g., major surgery, medical hospitalization, trauma) suggest that impact of these factors on VTE may be less substantial among NH residents. Objective: To use the longitudinal population-based resources of the Rochester Epidemiology Project (REP) to investigate the contribution of multiple clinical characteristics to risk of VTE among NH residents. Methods: We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1988 through 2005 (N=2,332). We then determined which individuals were resident of a local NH at time of VTE symptom onset, regardless of location of symptom onset (i.e., individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=269), we identified 2 same sex Olmsted County residents of similar age and duration of medical history who were also resident of a local NH at the time of the case's VTE event (i.e., index date) (N=538). We reviewed the detailed provider-linked medical records of NH VTE cases and NH non-VTE controls for 3 months before index for information on multiple characteristics identified or hypothesized as contributing to VTE risk in studies of the general population and other at-risk subgroups by our group and others (e.g., patient demographics, body mass index, major surgery, hospitalization for acute medical illness, outpatient surgical procedures, trauma/fracture, leg paresis, active cancer, superficial vein thrombosis, varicose veins, infections, diabetes mellitus, coronary artery disease, congestive heart failure, and multiple medications, including anticoagulants, statins, beta-blockers, ACE inhibitors and angiotensin II receptor antagonists). We tested and estimated the odds ratio associated with each factor using step-wise conditional logistic regression. Variables for which <10 cases or <10 controls exhibited the characteristic were excluded from analysis. Results: The first five variables to enter the model were urinary tract infection, active cancer, superficial vein thrombosis, pneumonia, and leg paresis. The respective odds ratios (95% confidence intervals) with all five in the model were 1.7 (1.2, 2.4); 2.1 (1.3, 3.5); 2.1 (1.3, 3.4); 1.9 (1.3, 2.8); 2.3 (1.3, 4.2); each p value was <0.01. Variables associated with high VTE risk in the general population (i.e., surgery, hospitalization for medical illness, trauma/fracture) were not included in the top five risk factors for NH residents. Conclusions: Infection is a potent VTE risk factor among NH residents. Our study results will help inform development of practice guidelines in the NH and stimulate future research on putative VTE mechanisms. REP data afford limited information on cognitive and physical disability, immobility, and need for NH care. Additional investigations are needed that combine information from clinical and NH assessments. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 5118 Background: Increased factor VIII:C (FVIII:C) and hypofibrinolysis are VTE risk factors, and beta-blockers and angiotensin converting enzyme (ACE) inhibitors reduce FVIII:C and enhance fibrinolysis, respectively. Objective: To test the hypotheses that beta-blockers and ACE inhibitors reduce VTE risk. Methods: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000 (n=1306), and one to two Olmsted County residents per case matched on age, event year and duration of prior medical history (n=1500). For cases and controls, we reviewed their complete medical history in the community for previously-identified VTE risk factors (e.g., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, superficial vein thrombosis and varicose veins), as well as body mass index (BMI), coronary artery disease (CAD), congestive heart failure (CHF), and the use of statins, beta-blockers, ACE inhibitors and angiotensin II receptor antagonist drugs. Using conditional logistic regression, we tested beta-blockers and ACE inhibitors/angiotensin II receptor antagonists for an association with VTE, both individually and after adjusting for age, BMI, previously-identified VTE risk factors, CAD, CHF and the use of statins. Results: Among cases and controls respectively, 191 and 173 received beta-blockers, and 171 and 154 received ACE inhibitors/angiotensin II receptor antagonists. Univariately, both beta-blockers (unadjusted OR=1.31; p=0.02) and ACE inhibitors/angiotensin II receptor antagonists (unadjusted OR=1.32; p=0.02) were modestly associated with increased VTE risk. However, after controlling for age, BMI, previously-identified VTE risk factors, CAD, CHF and the use of statins, beta-blockers (OR=1.06; 95% CI: 0.74, 1.51; p=0.75) and ACE inhibitors/angiotensin II receptor antagonists (OR=0.94; 95% CI: 0.65, 1.37; p=0.75) were no longer associated with VTE. Conclusions: Beta-blockers and ACE inhibitors/angiotensin II receptor antagonists do not appear to be protective against VTE. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2984 Poster Board II-960 In previous studies of venous thromboembolism (VTE) among all residents of Olmsted County, MN, the odds of VTE associated with surgery, medical hospitalization, or active cancer were extremely high (Univariate odds ratio [OR] =14.6; 4.6, and 8.4 respectively). We also showed that nursing home (NH) residency was an independent risk factor for VTE (OR =5.6). From a clinical practice perspective, it is important to identify which NH residents are at risk of VTE. While it might be assumed that, similar to estimates for the population generally, surgery, medical hospitalization, and cancer are associated with increased risk of VTE within the NH population, the answer remains unclear. We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1998-2005 (N=1168). We then determined which individuals were resident of a local NH at time of symptom onset, regardless of location of symptom onset (i.e., for purposes of this study, individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=96), we identified 2 same sex Olmsted County residents of similar age and duration-of-medical-history who were resident of a local NH at the time of the case's VTE event (i.e., index date) (N=192). The detailed provider-linked medical records of NH VTE cases and NH non-VTE controls were reviewed for 3 months before index for surgery or medical hospitalization and for 6 months surrounding index for active cancer. Using conditional logistic regression, we tested and estimated the odds ratio associated with each of these potential risk factors. The proportions of NH VTE cases and NH non-VTE controls with surgery (33%, 28%), medical hospitalization (44%, 46%), and active cancer (12%, 9%) were similar. Univariate odds ratios (95% confidence intervals) and p values for surgery, medical hospitalization, and active cancer were 1.5 (0.7-3.1), p=0.30; 1.1 (0.6-2.1), p=0.74; and 1.4 (0.6-3.2), p=0.46 respectively. Compared to the entire Olmsted County population, the odds of VTE associated with surgery, hospitalization, and cancer are surprisingly much lower for NH residents. Additional investigation is needed to characterize the subset of NH residents at increased risk of VTE. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Venous stasis syndrome (VSS) is a relatively common long-term sequelae of deep vein thrombosis (DVT), although it frequently is noted in individuals with no prior history of DVT. Objective: To evaluate whether: (1) venous stasis syndrome (VSS) is associated with a prior history of DVT; (2a) venous outflow obstruction (VOO) and/or (2b) venous valvular incompetence (VVI) are associated with DVT; and (3) VSS is associated with VVI and/or VOO. Design: Case-control study nested within a population-based inception cohort study. Population: 230 residents of Olmstead County, MN (OCM) with a first lifetime VTE over the 25-year period, 1966 – 1990 (cases), and 135 age, gender and year of incident VTE-matched OCM residents without prior history of VTE (controls). Measurements: Physical examination and patient questionnaire for symptoms or signs of VSS, and strain gauge outflow plethysmography, continuous wave venous Doppler ultrasound, and passive venous drainage and refill testing for VOO and VVI performed between 1996 – 1998. Results: Of the 365 study participants, 43 (12%) had VOO, 136 (37%) had VVI, and 265 (73%) had VSS. In multivariate logistic regression analyses: (1) age at the follow-up visit [OR Δper 10 years: 1.70 (1.41, 2.04)], prior DVT in the affected limb [OR: 4.03 (2.32, 7.01)], and presence of prior varicose veins [OR: 4.36 (1.84, 10.31)] were significantly associated with VSS; (2a) age at the follow-up visit [OR Δper 10 years (95% CI): 1.84 (1.39, 2.44)] and prior DVT in the affected limb [OR: 5.01 (2.61, 9.63)] were significantly associated with VOO; (2b) prior DVT in the affected limb (OR: 3.91 (2.56, 5.97)], presence of prior varicose veins [OR: 2.19 (1.32, 3.63)] and symptoms of VSS prior to incident DVT [OR: 3.42 (1.46, 8.00)] significantly increased the odds for VVI; and (3) VOO (p=0.004) and VVI (p<0.0001) were highly associated with VSS. Having a DVT in the left leg was associated with a greater odds of developing VOO, VVI or VSS in that leg when compared to their association with right leg DVT (OR: 6.69 vs. 3.65; 4.82 vs. 3.09; 4.71 vs. 3.97, respectively). Interestingly, prior DVT in the opposite leg was associated with an increased odds of subsequent VVI [OR: 2.00 (1.28, 3.10) and VSS [OR: 2.20 (1.31, 3.70)], but not VOO, in the test leg. Conclusions: Prior DVT imparts an increased risk for subsequent VSS, likely due to VOO and/or VVI. The odds of VOO or VSS increases with age. Presence of varicose veins increases the odds for VVI and VSS. We speculate that the increased odds of left sided VOO, VVI and VSS in patients with prior DVT may be secondary to May-Thurner syndrome. The increased odds of VVI and VSS in the limb opposite to the one affected by prior DVT could reflect occult DVT in the test limb, inferior vena cava thrombosis, or other mechanisms leading for VVI and VSS.

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Δ13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain–lambda (IgL-λ, and Δ13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-λ translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Δ13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Δ13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.

Abstract Background: Recent trends in the incidence of venous thromboembolism (VTE), including idiopathic vs. non-idiopathic VTE, have not been well described. Objective: To estimate the incidence of deep vein thrombosis (DVT) and pulmonary embolism with or without DVT (PE), and describe trends in incidence. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident DVT and PE over the 35-year period, 1966–2000 (n=3342). For all cases, the complete medical records in the community were reviewed for demographic and baseline characteristics previously identified as risk factors for VTE. Generalized linear models assuming a Poisson error structure, and using a log link function, and a log (population) offset will be used to assess the relationship of crude incidence rates to gender, year of diagnosis and age at diagnosis. Results: The overall average age- and sex-adjusted annual VTE incidence was 122 per 100,000 person-years (DVT, 56 per 100,000; PE, 66 per 100,000), with higher age-adjusted rates among men than women (134 versus 115 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 4 to 1110 per 100,000 for age groups 0–19 to 90–110 years. Compared to the 5-year period, 1981–85 (when non-invasive diagnostic testing became routinely available), the overall VTE incidence through 2000 remains unchanged. However, the DVT incidence and the PE incidence significantly increased and decreased, respectively, adjusting for age and gender (p<0.001 for both). The overall age- and sex-adjusted annual incidence of idiopathic VTE was 11.7 per 100,000 person-years (DVT, 6.6 per 100,000; PE, 5.1 per 100,000), with age-adjusted rates also higher among men than women (15.1 vs. 9.1 per 100,000). Interestingly, again compared to 1981–85, idiopathic VTE incidence decreased for 1991–95 (p=0.001) and 1996–2000 (p=0.32), adjusting for age and gender. Idiopathic DVT incidence decreased for 1991–95 (p=0.09), and idiopathic PE incidence decreased for both 1991–95 (p=0.004) and 1996–2000 (p=0.03). The overall age- and sex-adjusted annual incidence of non-idiopathic VTE was 109.4 per 100,000 (DVT, 48.4 per 100,000; PE, 60.7 per 100,000), again, with age-adjusted rates higher in men than women (115.1 vs. 106.8 per 100,000). Non-idiopathic DVT incidence increased steadily since 1981–85 (p=0.006, p<0.001, and p<0.001 for increasing DVT incidence for 1986–1990–1991–1995–1996–2000, respectively, adjusting for age and gender). Non-idiopathic PE incidence, however, remained unchanged for 1986–2000. Conclusions: VTE remains a major national health problem, especially among the elderly. Despite improved VTE prophylaxis efficacy and utilization, the overall incidence of VTE remains unchanged. However, the decreasing incidence of idiopathic DVT, and particularly idiopathic PE (with its associated poor survival) raises the possibility that the total number of VTE(PE)-related deaths may also be decreasing, albeit slightly. This hypothesis requires formal testing. The increasing or steady incidence of non-idiopathic DVT and PE, respectively, suggests the need for more widespread, effective VTE prophylaxis.