Bailey, Kent R.

Abstract BACKGROUND Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.

Abstract Background: Active cancer is an independent predictor of recurrent venous thromboembolism (VTE; hazard ratio=2.2–4.2). However, whether the risk of VTE recurrence among active cancer patients can be further stratified by tumor site or presence of metastases is uncertain. Objectives: To estimate and compare the cumulative incidence of VTE recurrence by tumor site and presence of metastases among active cancer patients with incident VTE. Study Design and Population: Retrospective cohort study of Olmsted County, MN residents with active cancer who lived >1 day after a first-lifetime deep vein thrombosis or pulmonary embolism over the 35-year period, 1966–2000 (n=418). 25 patients with oral (6), bone (1), skin (4), soft tissue (3), eye (1) and other/unknown (10) were excluded, leaving 393 remaining patients. Measurements: Baseline demographic and clinical characteristics, tumor site, presence and location of tumor metastases, and date of first recurrent VTE. Tumor site and metastases were tested as potential predictors of time-to-recurrent VTE using the Cox proportional hazards model. Results: 114 of 393 patients with active cancer developed recurrent VTE over 764 person-years of follow-up. The cumulative incidence of recurrent VTE at seven, 30, 90, and 180 days, 1, 5, and 10 years was 1.9%, 10.3%, 18.3%, 22.3%, 28.7%, 44.5%, and 53.5%, respectively. After adjusting for age and gender, tumor site was an independent predictor of first VTE recurrence (p<0.01). The hazard of VTE recurrence was over 2-fold higher for lung cancer patients compared to the lowest recurrence group (kidney, bladder and other genitourinary cancer; HR=2.04, 95% CI: 0.88, 4.70, p=0.096), and the hazard for brain and pancreatic cancer was nearly 2-fold higher (HR=1.9 for each, p=0.22, 0.24, respectively). The hazard of recurrence among hematological; breast and ovarian; gastric, colon, and liver; and prostate cancer patients did not differ significantly from the lowest recurrence group. Univariately, the presence of metastases at cancer diagnosis was not associated with recurrent VTE (HR=1.16; 95% CI: 0.79, 1.69, p=0.45). Conclusions: Tumor site is an independent predictor of VTE recurrence after adjusting for age and gender. In particular, lung, brain and pancreatic cancer patients have the highest risk for recurrence and these patients should be considered for secondary prophylaxis. Disease severity, as reflected by metastatic disease at cancer diagnosis, is not a predictor of recurrence.

Abstract Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. Consequently, the effect of heparin anticoagulation intensity on short-term VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain. Objectives: To test standard heparin anticoagulation intensity, using activated partial prothrombin time (APTT) data, as an independent predictor of 14-day VTE recurrence. Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving one day) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all APTT and platelet count values. Using these and other measures of standard heparin therapy as time-dependent variables, we tested the intensity of heparin anticoagulation as an independent predictor of 14-day VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling. Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 23 recurred within 14 days. In the multivariate analysis, the independent predictors of 14-day recurrence included female gender (HR=3.06, 95%CI: 1.05, 8.91; p=0.04) and neurologic disease with extremity paresis (HR=6.01, 95%CI: 1.93, 18.66; p<0.01); the hazard of recurrence was marginally increased for active cancer (HR=2.21, p=0.13). Warfarin therapy (HR=0.44, p=0.11) and a therapeutic APTT within the first 24 hours of therapy (HR=0.41, p=0.08) were marginally protective, but age, body mass index, time interval between VTE onset and start of heparin, and other measures of heparin anticoagulation intensity (e.g., proportion of time in therapeutic APTT range, etc) were not predictors of recurrence. Three patients developed new and persistent thrombocytopenia beginning 2, 4 and 5 days after starting heparin, respectively and prior to VTE recurrence. Conclusions: VTE recurrence is uncommon within 14 days after starting heparin therapy. Female gender and neurologic disease with extremity paresis are independent predictors of 14-day recurrence, and active cancer may be an additional predictor. Warfarin therapy and a therapeutic APTT within the first 24 hours may predict a reduced recurrence risk. However, other measures of heparin anticoagulation intensity were non-predictive. Heparin-induced thrombocytopenia may partially account for early VTE recurrence.

Abstract Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. However, the independent effect of warfarin anticoagulation intensity on VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain. Objectives: To test warfarin anticoagulation intensity, using international normalized ratio (INR) data, as an independent predictor of 6-month VTE recurrence. Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving 14 days without VTE recurrence) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all INR values. Using these and other measures of standard warfarin therapy as time-dependent variables, we tested the intensity of warfarin anticoagulation (expressed as the cumulative percent of time with an INR at or above 2.0 [or at or above 1.5] while on warfarin) as an independent predictor of 6-month VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling. Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 52 recurred within 15–180 days. In the multivariate analysis, the independent predictor of 6-month recurrence was active cancer (HR=3.98, 95% CI: 2.12, 7.45; p<0.01); age, gender, body mass index and neurologic disease with extremity paresis were not predictors of VTE recurrence. In models that included presence or absence of warfarin therapy along with proportion of time with an INR ≥2, this latter intensity variable was protective (HR=0.16 for 100% versus 0% of time, p=0.02) against recurrence, while mere presence of warfarin therapy (HR =0.72, p= 0.56) was not. Similar results were obtained when intensity was represented as proportion of time with an INR ≥1.5 (HR=0.17, p=0.02). Interestingly, a therapeutic APTT within the first 24 hours of heparin therapy also was protective against 6-month recurrence (HR=0.45, p=0.02). Conclusions: Active cancer is an independent predictor of 6-month VTE recurrence. Warfarin therapy with a higher proportion of time with an INR ≥1.5 or ≥2 offers similar protection against recurrence. A rapid heparin-response (as reflected by a therapeutic APTT within 24 hours of heparin therapy) also is a predictor of reduced 6-month recurrence, possibly reflecting lower factor VIII activity at the acute incident VTE event. Gender is not a predictor of long-term recurrence.

Abstract Background: While several uncommon disorders (e.g., myeloproliferative diseases, connective tissue disease, etc.) have been suggested as potential risk factors for VTE, the independence and magnitude of any risk is uncertain. Objective: To test uncommon characteristics as potential independent risk factors for VTE, and estimate the magnitude of risk for each. Methods: Using the resources of the Rochester Epidemiology Project, we identified all incident cases of deep vein thrombosis and pulmonary embolism over the 6-year period, 1992–1997. For each objectively confirmed case (n=562), we identified up to two Olmsted County residents without VTE who most closely matched a case on age, gender, and medical record number (n=755). Because medical record numbers are assigned sequentially, such matching assures a similar duration of medical follow-up. For all cases and controls, we reviewed the complete medical records in the community for over 125 baseline characteristics which were tested for an association with VTE using conditional logistic regression. Results: The mean ± SD (range) ages for cases and controls were 65.71 ± 18.85 (0–102) and 64.90 ± 18.66 (0–102) years, respectively, and 55.5% were female. Novel univariate risk factors for incident VTE included former tobacco smoker, ischemic heart disease, valvular heart disease, chronic lung disease, all-cause pulmonary hypertension, chronic renal disease, myeloproliferative disorders, any infection, femoral artery catheterization (angiography or percutaneous intervention), ICU admission and angiotensin converting enzyme (ACE) inhibitor therapy. Among infections, septicemia, pneumonia, and ENT, cardiovascular, GI, urinary tract and skin/soft tissue infections were univariately associated with VTE; reproductive tract infection was not. Diabetes mellitus, hyperlipidemia, lipid-lowering drugs (including statins), inflammatory bowel disease, asthma, connective tissue disease, and influenza were not univariately associated with VTE, and beta-blocker therapy was not protective. A multivariate analysis will test these characteristics as potential independent VTE risk factors. Conclusions: Several novel characteristics are univariately associated with VTE. Such novel characteristics may provide new insights into VTE mechanisms if, upon further analysis, these characteristics are independent VTE risk factors.

Abstract Confinement to a nursing home (NH) is an independent risk factor for VTE and accounts for 13% of all VTE occurring in the community, but the question of which NH residents are at risk is largely unanswered. Objective: To determine VTE risk factors among NH residents. Methods: Using the Minnesota State Case Mix Review Program Public Research Files, we performed a case-control study of all Olmsted County, MN NH patients with an ICD-9 code-identified diagnosis of VTE from 1988–1994. From the same source, we identified one age-, sex-matched control and used conditional logistic regression to estimate odds ratios for an association of VTE with 46 characteristics assessed in the Minnesota Case Mix data. Results: Univariate associations between characteristics and odds of VTE are described below. Significantly increased odds were observed for residents assessed following hospitalization (a nearly 4-fold increase, p=0.002, Table) and residents considered incapable of self-preservation (i.e., unable to cope with potentially harmful situations) (> 2.0 fold increase, p=0.03). Non-significant 2–3 fold increased odds were observed for limitations in certain specific Activities of Daily Living (ADL) (including walking and dressing) and for limitations in more than 3 ADLs. Similar increased odds were observed for residents using a wheelchair, taking more than 3 oral medications, enrolled in professional activity programs, and needing behavior management. Conclusions: Need for assistance (especially problems with immobility), lack of self preservation, and recent hospitalization may identify a subset of NH residents that are at especially high VTE risk and who may warrant consideration of prophylaxis. Univariate VTE Risk Factors for Nursing Home Residents Characteristic Odds Ratio 95% CI P-value Oral medications > 3 3.00 0.97-9.30 0.06 Activities of Daily Living High/Medium (4-8) vs. low (0-3) 2.20 0.76-6.33 0.14 Help dressing 2.75 0.88-8.64 0.08 Help walking 3.00 0.61-14.86 0.18 Wheelchair use 2.50 0.97-6.44 0.58 Needs behavior management 3.00 0.62-14.86 0.18 Help toileting 2.00 0.68-5.85 0.20 Lack of self-preservation 2.33 1.07-5.10 0.03 Transfer from hospital 3.86 1.68-8.86 0.0015 Anti-depressant drugs 0.50 0.19-1.33 0.16 Professional activity program 2.25 0.69-7.3 0.18

Abstract Objective: Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Methods: Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. Results: WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). Conclusion: In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.

Abstract Introduction: Hospitalization-associated VTE attack (incident plus recurrent VTE) rates over the 6-year period, 2005-2010, did not change significantly despite achieving near-universal in-hospital VTE prophylaxis; 75% of these VTE events occurred after hospital discharge with a median of 19.5 days from hospital discharge to VTE. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively, suggesting that VTE prophylaxis was inadequate. However, the hospital population that would benefit most from post-hospitalization VTE prophylaxis is uncertain. Our study aim was to test hospital length of stay (LOS) as a potential predictor of post-hospital-discharge incident or recurrent VTE. Methods: Using the resources of the Rochester Epidemiology Project, we identified all unique Olmsted County, MN residents hospitalized at least once at a Rochester, MN Mayo Clinic hospital and all such residents with objectively-diagnosed occurrence of first or recurrent VTE during hospitalization or within 92 days after hospital discharge, 2005-2010. We tested LOS as a potential predictor of post-hospital-discharge VTE (conditional on surviving to hospital discharge free of VTE) using the Anderson-Gill version of Cox regression modeling and adjusting for age, sex, any surgery performed during that hospitalization, and Charlson Comorbidity Index calculated from conditions recorded from 1/1/2005 until the day of hospital discharge. Results: Over the period, 2005-2010, 31,588 unique Olmsted County residents were hospitalized at least once at a Rochester Mayo Clinic hospital. The distribution of LOS was: 1-2 (3.8%), 3 (24.2%), 4 (23.3%), 5 (16.4%), 6 (8.8%), 7-9 (12.4%), 10-19 (8.4%) and 20+ (2.3%). Of the 253 VTE events identified within 92 days post-hospital discharge, 6, 29, 31, 38, 38, 53, 42 and 16 had been hospitalized for 1-2, 3, 4, 5, 6, 7-9, 10-19 and 20+ days, respectively. The hazard ratios (HR) for post-hospital-discharge VTE were similar for hospital LOS ≤4 days; compared to LOS ≤3 days, the HRs were significantly increased for hospital LOS of 5 (HR=1.78), 6 (HR=2.86), 7-9 (HR=2.71), 10-19 (HR=3.16) and 20+ (HR=4.20) days (Table 1). Conclusions: The adjusted hazards of post-hospital discharge VTE for hospital LOS > 4 days were significantly increased 1.8 to 4.2-fold compared to LOS ≤3 days, suggesting that hospital LOS may be useful for identifying hospitalized patients suitable for longer duration VTE (including post-discharge) prophylaxis. Future studies should be aimed at identifying additional predictors of post-hospital-discharge VTE such that extended prophylaxis can be targeted to those patients who would benefit most. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Active cancer without or with chemotherapy is associated with a 4- to 6.5-fold increased risk for VTE 1. However, cancer-associated VTE incidence may be under- or overestimated by reports that linked cancer registry data to an anticoagulation clinic database or to hospital discharge diagnosis codes 2–5. Objective: To estimate the incidence of VTE in active cancer in a well-defined geographic population that includes the full spectrum of VTE events (including rapidly fatal events) occurring in the community. Methods: Using the longitudinal resources of the Rochester Epidemiology Project and Mayo Clinic Tumor Registry, we identified all Olmsted County, MN residents with incident VTE by review of their complete medical records in the community 6, and all residents with active cancer (by cancer site), over the 28-year period, 1973–2000. Using residents with active cancer within the three months prior or subsequent to incident VTE as the numerator, and all residents with active cancer as the denominator, we estimated the incidence of VTE in active cancer, both overall and for the subsets of pancreatic cancer, brain cancer and lymphoma. Results: Over 78,236 active-cancer person-years, 595 Olmsted County residents developed incident VTE. The overall active cancer-associated VTE incidence was 760 per 100,000 person-years (95% CI: 701, 824), about 6.5-fold higher than the general population 7. Over 473, 983 and 4,258 pancreatic cancer, brain cancer and lymphoma person-years, respectively, 51, 18 and 46 residents developed incident VTE. The pancreatic cancer-, brain cancer- and lymphoma-associated VTE incidence rates were 10,784 (95% CI: 8029, 14,179), 1,831 (95% CI: 1085, 2,893) and 1,080 (95% CI: 791, 1,441) per 100,000, respectively. Overall, cancer-associated VTE incidence increased with age, and for all ages, men had a higher VTE rate than women. We observed a much higher pancreatic cancer-associated VTE incidence than previously reported. Conclusions: The incidence of VTE in individuals with active cancer (especially pancreatic cancer) is higher than the general population. The incidence of VTE in patients with pancreatic cancer is higher than previously estimated.