Petterson, Tanya M.

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.

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.

Abstract Abstract 2256 Background: The incidence of venous thromboembolism (VTE) may be increasing due to the obesity epidemic. Objective: To estimate the incidence of VTE and describe trends in incidence adjusted for the population's increase in BMI. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis (DVT) or pulmonary embolism (PE) over the 13-year period, 1988–2000 (n=1,400). Age and BMI at VTE diagnosis and gender were collected for all cases. Age was categorized into 10 year intervals. Using a model for the population distribution of BMI derived from several (n=6) non-VTE Olmsted County cohorts (n=8,011 individuals), we calculated the probability of falling into each of five BMI categories (<18.5, 18.5–24, 25–29, 30–34, 35+) for each age, gender and calendar year. In Olmsted County in the median age group, the prevalence of BMI >30 kg/m2increased from approximately 15% in 1980 to 36% in 2000. We applied these probabilities to the decennial census data for 1980, 1990, 2000 using linearly interpolated census values for intra-census years to obtain Olmsted County age/sex/calendar year/BMI category denominators. Generalized linear modeling assuming a Poisson error structure, and using a log link function, and a log (population) offset was used to assess the relationship of crude incidence rates to gender, year of diagnosis, age and BMI. Results: The overall average age- and sex-adjusted annual VTE incidence was 120 per 100,000 person-years (DVT: 66 per 100,000; PE: 54 per 100,000), with higher age-adjusted rates among men than women (129 versus 113 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 3 to 1,079 per 100,000 for age groups 0–19 to 90–110 years. Age and sex-adjusted VTE incidence increased by increasing BMI category (88, 112, 106, 150, and 195 per 100,000 person-years, respectively, by increasing BMI category). Unadjusted for BMI, VTE incidence was unchanged from 1988 through 2000 (p=0.70). After adjusting for age, gender and calendar year, VTE incidence increased with increasing BMI (p<0.0001). The calendar year incidence slope estimate decreased numerically from 3% per decade to minus 4% per decade after adjusting for increasing BMI, remaining nonsignificant (p=0.57). Conclusions: VTE remains a major national health problem, especially among the obese. Despite the dramatically increasing population BMI, and the significant association of BMI category with VTE incidence, the overall incidence of VTE remained unchanged over the timeframe, 1988–2000. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 150 Background: While bivariate interactions between Factor V Leiden, prothrombin G20201A and hereditary deficiency of antithrombin, protein C and protein S compound VTE risk, whether other gene-gene interactions are associated with VTE is largely unknown. Objective: To test gene-gene interactions for an association with VTE. Methods: Cases (n=1004) were Mayo Clinic European-American patients of non-Hispanic ancestry with objectively-diagnosed VTE in the absence of active cancer, venous catheter or antiphospholipid antibodies. Controls (n=1066) were Mayo Clinic outpatients without VTE who were frequency-matched on case age, gender, race, MI/stroke status and state of residence. We selected candidate genes relevant to the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways, focusing on platelet, monocyte, neutrophil and endothelial cell agonists, receptors, ligands, signal transduction and adhesion molecules, granule contents and effectors; plasma proteases and inhibitors; matrix metalloproteases; inflammatory cytokines and receptors; estrogen, progesterone and androgen receptors; co-regulators and enzymes related to estrogen metabolism; important enzymes for catechol, homocysteine, thromboxane A2 and prostacyclin biosynthesis and metabolism; and HMG CoA reductase. For these genes (n=780), we selected all non-synonymous coding single nucleotide polymorphisms (SNPs) with minor allele frequency ≥0.5%; the remaining SNPs were selected using an LD tagging algorithm (Carlson et al. AJHG 2004); 558 ancestry-informative markers were also included (total n=13,237 SNPs). Leukocyte genomic DNA was genotyped using a custom Illumina Infinium iSelect chemistry and platform, including appropriate controls. For these analyses, all pairwise SNP-SNP interactions for 12,313 SNPs were tested using logistic regression. In addition, we tested all Factor V Leiden -, prothrombin G20210A - and ABO non-O blood group - SNP interactions. Results: The mean ± SD case and control ages were 55.3 ± 16.4 and 56.5 ± 15.9 years, respectively, and 51% were female. Analysis of ancestry-informative markers gave no evidence of population stratification. Among almost 76 million pairwise interactions tested, 504, 44 and 8 SNP-SNP interactions reached p-values ≤ 1E-5, 1E-6, and 1E-7 respectively; none reached the Bonferroni statistical significance threshold (≤ 6.6E-10). The gene-gene pairwise interactions with p-values ≤ 1E-7 included: Leptin receptor - Estrogen receptor 1, α1 Antichymotrypsin - β2 glycoprotein 1, CRADD(caspace) - B1 Bradykinin receptor, ILF10 - Prolactin receptor and GFRA2(TGFβ neurotrophic factor receptor) - Bactericidal permeability-increasing protein. Gene-gene pairwise interactions with the lowest p-value for Factor V Leiden -, prothrombin G20210A - and ABO non-group O - were Protein kinase C beta (2.1E-5), von Willebrand Factor (7.6E-4) and Phospholipase C gamma-2 (6.7E-4), respectively. Conclusion: Pairwise gene-gene interaction analyses suggest potential associations between VTE and novel genes and gene pathways. These potential associations require confirmation in future replication studies. Disclosures: No relevant conflicts of interest to declare.

AbstractNursing home (NH) residency is an independent risk factor for venous thromboembolism (VTE), but the VTE burden within the NH population is uncertain. This study estimates VTE incidence and VTE-associated mortality among NH residents. We identified all NH residents in any NH in Olmsted County, Minnesota, United States, 1 October 1998 to 31 December 2005 and all first lifetime VTE among county residents to estimate VTE incidence while resident of local NHs (NHVTE), using Centers for Medicare and Medicaid Services Minimum Data Set and Rochester Epidemiology Project resources. We tested associations between NHVTE and age, sex and time since each NH admission using Poisson modelling. Additionally, we tested incident NHVTE as a potential predictor of survival using Cox proportional hazards, adjusting for age, sex and NH residency. Between 1 October 1998 and 31 December 2005, 3,465 Olmsted County residents with ≥1 admission to a local NH, contributed 4,762 NH stays. Of the 3,465 NH residents, 111 experienced incident NHVTE (2.3% of all eligible stays), for an overall rate of 3,653/100,000 NH person-years (NH-PY). VTE incidence was inversely associated with time since each NH admission, and was highest in the first 7 days after each NH admission (18,764/100,000 NH-PY). The adjusted hazard of death for incident NHVTE was 1.90 (95% confidence interval [CI]: 1.38–2.62). In conclusion, VTE incidence among NH residents was nearly 30-fold higher than published incidence rates for the general Olmsted County population. VTE incidence was highest within 7 days after NH admission, and NHVTE was associated with significantly reduced survival. These data can inform future research and construction of clinical trials regarding short-term prophylaxis.

Background: Certain diseases can occur with and without a trigger. We use Venous Thromboembolism (VTE) as our example to identify genetic interaction with pregnancy in women with VTE during pre- or postpartum. Pregnancy is one of the major risk factors for VTE as it accounts for 10% of maternal deaths. Methods: We performed a whole genome association analysis using the Cox Proportional Hazard (CoxPH) model adjusted for covariates to identify genetic variants associated with the time-to-event of VTE related to pre- or postpartum during the childbearing age of 18–45 years using a case-only design in a cohort of women with VTE. Women with a VTE event after 45 years of age were censored and contributed only follow-up time. Results: We identified two intragenic single nucleotide polymorphisms (SNPs) at genome-wide significance in the PURB gene located on chromosome 7, and two additional intragenic SNPs, one in the LINGO2 gene on chromosome 9 and one in RDXP2 on chromosome X. Conclusions: We showed that the time-to-event model is a useful approach for identifying potential hazard-modification of the genetic variants when the event of interest (VTE) occurs due to a risk factor (pre- or post-partum).

Key PointsApproximately 500 000 US VTE events occur annually; approximately one-half are related to current or recent hospitalization. VTE attack rates (2005-2010) did not change despite near-universal in-hospital VTE prophylaxis, possibly due to short prophylaxis duration.

Abstract Background Clostridium difficile is a major cause of diarrhea in thoracic organ transplant recipients. We investigated the epidemiology, risk factors, and outcome of Clostridium difficile infection ( CDI ) in heart and heart‐lung transplant ( HT ) recipients. Methods This is a retrospective study from 2004 to 2013. CDI was defined by diarrhea and a positive toxigenic C. difficile in stool measured by toxin enzyme immunoassay (2004‐2006) or polymerase chain reaction (2007‐2013). Cox proportional hazards regression was used to model the association of risk factors with time to CDI and survival with CDI following transplantation. Results There were 254 HT recipients, with a median age of 53 years ( IQR , 45‐60); 34% were female. During the median follow‐up of 3.1 years ( IQR , 1.3‐6.1), 22 (8.7%) patients developed CDI . In multivariable analysis, risk factors for CDI were combined heart‐lung transplant ( HR 4.70; 95% CI , 1.30‐17.01 [ P =.02]) and retransplantation ( HR 7.19; 95% CI , 1.61‐32.12 [ P =.01]). Acute cellular rejection was associated with a lower risk of CDI ( HR 0.34; 95% CI , 0.11‐0.94 [ P =.04]). CDI was found to be an independent risk factor for mortality ( HR 7.66; 95% CI , 3.41‐17.21 [ P <.0001]). Conclusions Clostridium difficile infection after HT is more common among patients with combined heart‐lung and those undergoing retransplantation. CDI was associated with a higher risk of mortality in HT recipients.