Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study

BACKGROUND: Oral estrogen use and elevated body mass index (BMI) increase the risk of venous thromboembolism (VTE). Recent data suggest that transdermal estrogen might be safe with respect to thrombotic risk. However, the impact of transdermal estrogen on the association between overweight (25 kg m(-2) < BMI < or = 30 kg m(-2)) or obesity (BMI >30 kg m(-2)) and VTE risk has not been investigated. METHODS: We carried a multicenter case-control study of VTE among postmenopausal women aged 45-70 years, between 1999 and 2005, in France. Case population consisted of women with a first documented idiopathic VTE. We recruited 191 hospital cases matched with 416 hospital controls and 62 outpatient cases matched with 181 community controls. RESULTS: The odds ratio (OR) for VTE was 2.5 [95% confidence interval (CI):1.7-3.7] for overweight and 3.9 (95% CI: 2.2-6.9) for obesity. Oral, not transdermal, estrogen was associated with an increased VTE risk (OR = 4.5; 95% CI: 2.6-7.7 and OR = 1.1; 95% CI: 0.7-1.7, respectively). Compared with non-users with normal weight, the combination of oral estrogen use and overweight or obesity further enhanced VTE risk (OR = 10.2; 95% CI: 3.5-30.2 and OR = 20.6; 95% CI: 4.8-88.1, respectively). However, transdermal users with increased BMI had similar risk as non-users with increased BMI (OR = 2.9; 95% CI: 1.5-5.8 and OR = 2.7; 95% CI: 1.7-4.5 respectively for overweight; OR = 5.4; 95% CI: 2.1-14.1 and OR = 4.0; 95% CI: 2.1-7.8 respectively for obesity). CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer an additional risk of idiopathic VTE in women with increased BMI. The safety of transdermal estrogen on thrombotic risk has to be confirmed.     

Effect of NFE2L2 genetic polymorphism on the association between oral estrogen therapy and the risk of venous thromboembolism in postmenopausal women

Oral, but not transdermal, estrogen therapy increases the risk of venous thromboembolism (VTE) in women who are past menopause. Data from the Estrogen and Thromboembolism Risk (ESTHER) study were used to investigate the effects of the genetic polymorphism of NFE2L2 rs6721961, which may impair Nrf2-dependent hepatic conjugation of estrogen metabolites. As compared with nonusers, the odds ratio (OR) for VTE in current users of oral estrogens was 2.5 (95% confidence interval (CI): 1.3-4.8) in patients with wild-type NFE2L2 and 17.9 (95% CI: 3.7-85.7) in those with the polymorphism (interaction, P = 0.01).     

ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case-control study.

OBJECTIVES: To examine possible associations of ABO blood types with the risk of venous thromboembolism (VTE) in pregnancy and the puerperium. PATIENTS AND METHODS: We conducted a nested case-control study within a cohort of 71,729 women who gave birth to 126,783 children in the North Jutland County, Denmark, from 1980 to 2001. We identified 129 cases with VTE in pregnancy (n = 61) or the puerperium (n = 68), and 258 controls with no VTE. We collected information on ABO blood groups and possible maternal confounding factors and estimated the relative risk [odds ratio (OR)]. RESULTS: Women with an A or AB blood group had elevated risk estimates of VTE in pregnancy or the puerperium compared with women with a O blood group [adjusted ORs 2.4, 95% confidence interval (CI) 1.3, 4.3, and 2.0, 95% CI 0.7, 5.8, respectively]. No increased risk estimate was found for group B (adjusted OR 1.2, 95% CI 0.5, 3.0). The increased risk estimates of VTE for blood groups A and AB appeared present in both pregnancy (adjusted ORs of 3.9, 95% CI 1.5, 9.7, and 2.2, 95% CI 0.4, 12.5) and in the puerperium (adjusted ORs of 2.4, 95% CI 1.0, 4.9 and 2.7, 95% CI 0.8, 9.3). Furthermore, blood groups A and AB appeared to be associated with increased risk estimates for both DVT and pulmonary embolism. CONCLUSION: Keeping the modest statistical precision of our study in mind, blood groups A and AB may be associated with increased risk estimates for VTE in pregnancy and the puerperium.     

Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23 796 consecutive autopsies

BACKGROUND: The relationship between atherothrombotic disease and venous thromboembolism (VTE) remains unclear. PATIENTS AND METHODS: In a cohort of 23,796 consecutive autopsies, performed using a standardized procedure and representing 84% of all in-hospital deaths between 1970 and 1982 in an urban Swedish population, we investigated the relationship between verified arterial thrombosis and VTE, with the hypothesis that patients with thrombosis in major artery segments have increased odds of VTE. RESULTS: We found an increased risk of VTE in patients with arterial thrombosis (Odds ratio; OR adjusted for gender and age 1.4, 95% confidence interval; CI 1.3-1.5) (P < 0.001). Patients with cervico-cranial and peripheral artery thrombosis had an excess risk even when controlling for age and major concomitant diseases. A negative association between coronary thrombosis and VTE in the univariate analysis (OR 0.7; 95% CI 0.6-0.8) (P < 0.001), was less pronounced in the multivariate analysis (OR 0.8; 95% CI 0.7-1.0) (P = 0.016). CONCLUSIONS: A positive association between atherothrombosis and VTE was confirmed, except in patients with coronary thrombosis, where IHD as competing death cause is a possible confounder. Our findings indicate a potential for directed prevention, but may also imply similarities in etiology.     

Venous thromboembolism after spinal cord injury: incidence, time course, and associated risk factors in 16,240 adults and children

OBJECTIVE: To analyze the incidence of venous thromboembolism (VTE) after spinal cord injury (SCI). DESIGN: Retrospective cohort analysis of all SCI cases (16,240) in California from 1991 through 2001. SETTING: All public hospitals in California. PARTICIPANTS: Subjects (cases) coded as having complete or incomplete SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Diagnosis of VTE or death within 91 days of the day of hospital admission. RESULTS: For all cases, the 91-day cumulative incidence of VTE was 5.4%. In a multivariate model, significant predictors of VTE included male sex (odds ratio [OR]=1.4; 95% confidence interval [CI], 1.2-1.7), African-American race (OR=1.6; 95% CI, 1.3-1.9), complete paraplegia versus tetraplegia (OR=1.8; 95% CI, 1.4-2.3), and presence of 3 or more comorbid conditions versus none (OR=1.6; 95% CI, 1.3-2.1). Age less than 14 years was predictive of not developing VTE (OR=0.2; 95% CI, 0.1-0.7). The incidence of VTE did not change significantly over the 11-year time period (P=.07), and VTE was not a significant predictor of death in the first 91 days after hospitalization. CONCLUSIONS: The incidence of VTE in SCI patients in California did not change between 1991 and 2001. We identified specific risk factors for VTE. Further studies are needed to determine if prompt initiation of medical prophylaxis in high risk subjects reduces the incidence of symptomatic VTE.     

Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study

Previous studies of selected patients have suggested a reduction in the risk of venous thromboembolism with the use of statins. The objective of this study is to evaluate the influence of statin use on the risk of venous thromboembolic (VTE) events. The study is a case-control study (EDITH: Etude des Déterminants et Interactions de la Thrombose Veineuse), designed to investigate the genetic and environmental risk factors of VTE. A total of 377 patients consecutively hospitalized in the Brest University Hospital for a documented VTE event, between May 2000 and May 2002, and 377 age- and sex-matched controls were studied. Statin use was associated with a 58% decreased risk of VTE [odds ratio (OR) 0.42; 95% confidence interval (CI) 0.23-0.76; P = 0.002]. Adjustment for age, gender, coronary heart disease, atherosclerothrombotic disease or current use of aspirin did not alter the result. Neither fibrates (OR 1.38; 95% CI 0.76-2.52; P = 0.26), nor thienopyridines (OR 1.07; 95% CI 0.48-2.41; P = 0.85) were associated with a reduced risk of VTE. Aspirin use tended to decrease the risk of VTE, but this result was not significant (OR, 0.66; 95% CI, 0.42-1.05). The use of statins is associated with a significant reduction in the risk of VTE, irrespective of age, gender, and past history of atherosclerothrombotic disease, as well as the use of aspirin. This possible protective effect of statins warrants further investigations.     

Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study

Cohort studies suggest that exposure to antipsychotic agents may be associated with an increased risk of venous thromboembolism (VTE). Few data concerning antidepressant drugs are available. Using a different methodological approach, the aim of this study was to estimate the association between neuroleptic and antidepressant drug use and the risk of VTE. We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We included 677 cases hospitalized with deep vein thrombosis and or pulmonary embolism with no major acquired risk factor for VTE, and 677 controls matched for gender and age. Drug exposure was defined as current use of drugs at admission. Neuroleptic exposure was associated with an increased risk of VTE (OR = 2.1, 95% CI 1.4-3.2). Among neuroleptics, antipsychotic agent use was associated with a 3.5-fold increased risk of VTE (OR = 3.5, 95% CI 2.0-6.2). No association was found between antidepressant drug exposure and the risk of VTE (OR = 1.1, 95% CI 0.9-1.5). In this hospital-based case-control study, exposure to antipsychotic drugs was associated with an increased risk of VTE. These results, added to previous results, suggest that clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. More studies are needed in order to further elucidate this adverse effect, and to determine the possible predisposing factors and the biological mechanisms involved.     

Risk of obstetric and thromboembolic complications in family members of women with previous adverse obstetric outcomes carrying common inherited thombophilias

Summary. Background: Factor (F)V Leiden and the prothrombin 20210A mutation (PTm) are associated with the occurrence of obstetric complications, including pregnancy‐related venous thromboembolism (VTE). It is not known whether family members of women with FV Leiden or PTm and previous obstetric complications have a higher risk of VTE or adverse obstetric outcomes. Methods: A retrospective family study including 563 relatives of 177 women with previous adverse outcomes carrying FV Leiden or PTm, referred between April 1993 and June 2010. A history of obstetric complications and VTE was obtained. Prevalence of VTE and obstetric complications in relatives with and without inherited thrombophilias was compared. Adjusted odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models that controlled for predictors (age, FV Leiden and PTm). Results: Relatives carrying FV Leiden had a significant and independent risk for obstetric complications (OR: 1.98, 95% CI 1.03–3.83); this risk was not observed in the presence of PTm (OR: 1.03, 95% CI 0.46–2.32). The presence of FV Leiden or PTm in heterozygosis was significantly and independently associated with the occurrence of VTE (OR: 5.2, 95% CI: 1.70–15.91). Severe thrombophilias were strong risk factors for VTE (OR: 23.2, 95% CI: 6.0–89.85). Male gender was a significant and independent risk factor for VTE (OR: 3.49, 95% CI: 1.51–8.05). The risk did not change when relatives of women with a previous pregnancy‐related VTE were excluded (OR: 3.49, 95% CI: 1.51–8.05). Conclusions: Knowledge of thrombophilia status may help to better define the obstetric and thromboembolic risks in asymptomatic family members of women who suffered from obstetric complications.     

Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy

BACKGROUND: A first thromboembolic event during pregnancy and puerperium is predisposed to by polymorphisms G1691A in the factor V gene (F5) (F5G1691A) and G20210A in the prothrombin gene (F2) (F2G20210A). OBJECTIVES: To study another potentially frequent thrombogenic polymorphism, C46T in the factor XII gene (F12) (F12C46T). Patients and methods: The 32 463 previously asymptomatic women included in the NOHA First cohort in their first pregnancy were investigated for these three polymorphisms. No other constitutional or acquired thrombophilic risk factor was studied. RESULTS: The overall incidence--absolute risk--of venous thromboembolic events (VTE) was 127 per 100,000 woman-years and was reduced to 22 per 100,000 women-years in women negative for the three polymorphisms (P < 0.0001). Homozygosity for F12C46T was associated with a significant relative risk (RR) of VTE [RR: 5.99, 95% confidence interval (95% CI): 2.1-17.3, P = 0.001], as was heterozygosity for F5G1691A (RR: 18.7, 95% CI: 8.3-42, P < 0.0001), heterozygosity for F2G20210A (RR: 14.3, 95% CI: 6.2-33.2, P < 0.0001), maternal age (RR: 1.18, 95% CI: 1.07-1.29, P = 0.0006), maternal body mass index (RR: 1.31, 95% CI: 1.11-1.55, P = 0.002), conceptus weight (percentiles adjusted for term of delivery; RR: 0.90, 95% CI: 0.88-0.93, P < 0.0001) and pre-eclampsia (RR: 3.03, 95% CI: 1.06-8.69, P = 0.039). CONCLUSIONS: Homozygosity for the C46T polymorphism of the F12 gene is associated with venous thrombosis during the first pregnancy/puerperium in previously asymptomatic women.     

The Rochester Coronary Heart Disease Project: effect of cigarette smoking, hypertension, diabetes, and steroidal estrogen use on coronary heart disease among 40- to 59-year-old women, 1960 through 1982

A population-based case-control study of coronary heart disease (CHD) risk in young women attributable to cigarette smoking, hypertension, diabetes, and steroidal estrogen use was conducted among residents of Rochester, Minnesota. All newly diagnosed cases of CHD (sudden unexpected death [SUD], N = 18; myocardial infarction [MI], N = 90; and angina, N = 133) among female Rochester residents 40 to 59 years of age during the years 1960 through 1982 were identified, and two community control subjects were matched for age and duration of community medical record. The overall adjusted odds ratio (OR) for the association between steroidal estrogen use and definite CHD (MI and SUD) was 0.6 (95% confidence interval [CI] = 0.2 to 1.3). Smoking (OR = 5.1; 95% CI = 2.3 to 11.6), hypertension (OR = 4.8; 95% CI = 2.3 to 10.2), and diabetes (OR = 8.4; 95% CI = 1.6 to 44.5) were strong risk factors for CHD events. If considered causal, cigarette smoking accounted for 64% of all MIs and SUDs in the community, hypertension accounted for 45%, and diabetes accounted for 13%. Although steroidal estrogen exposure reduced CHD among these women by 14%, giving steroidal estrogens to all women in this age group might reduce the population rates of MI by as much as 45%.     

Prothrombin A19911G polymorphism and the risk of venous thromboembolism

BACKGROUND: The A > G polymorphism at position 19911 of the prothrombin gene is associated with increased plasma prothrombin levels but its role as a risk factor for venous thromboembolism (VTE) is not established. OBJECTIVE: To investigate the role of prothrombin 19911 A > G polymorphism in the risk of VTE in patients with heterozygous prothrombin 20210GA or factor (F) V Leiden and in those without thrombophilia. PATIENTS AND METHODS: Case-control study of 793 patients with prothrombin 20210 GA (n = 167) or FV Leiden (n = 198), and without thrombophilia (n = 428), and of 795 healthy individuals with the corresponding coagulation profile, investigated for the presence of prothrombin 19911 A > G. Plasma prothrombin levels were measured in 342 individuals. RESULTS: Prothrombin 19911 A > G did not increase the risk of VTE in carriers of prothrombin 20210 GA [odds ratio (OR) 1.2, 95% CI (95% CI) 0.8-1.8] but significantly increased the risk in carriers of FV Leiden (OR 2.1, 95% CI 1.3-3.4) and in patients without thrombophilia (OR 1.5, 95% CI 1.0-2.2). Higher plasma prothrombin levels in carriers of prothrombin 19911 A > G polymorphism than in non-carriers were found among individuals without thrombophilia (P =0.05) and with FV Leiden (P = 0.07), but not in carriers of prothrombin 20210 GA (P = 0.2). CONCLUSIONS: Prothrombin 19911 A > G polymorphism was independently associated with a 1.5-fold increased risk of VTE and increased 2-fold the risk of VTE associated with FV Leiden, both increases statistically significant. No effect was observed in carriers of prothrombin 20210 GA, perhaps because this polymorphism has a stronger influence on plasma prothrombin levels than the prothrombin 19911 polymorphism.     

Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women

BACKGROUND: Cohort studies suggest an association between variation in the estrogen receptor-alpha gene (ESR1) and cardiovascular disease (CVD), but data are lacking for the effect of variation in the estrogen receptor-beta gene (ESR2). METHODS: Three polymorphisms of the ESR2 gene, and their associated haplotypes, were evaluated in 296 white women from the Women's Health Study and 566 white men from the Physicians' Health Study who developed CVD [myocardial infarction (MI) or ischemic stroke], each matched 1:1 to a member of the cohort study who remained free from CVD. Blood samples and cardiovascular risk information were collected at baseline. RESULTS: Women, but not men, who developed CVD or MI, but not ischemic stroke, were more likely to have the rs1271572 polymorphism variant T allele (P = 0.05 and 0.02) and less likely to have the rs1256049 polymorphism variant A allele (P = 0.003 and 0.004). No associations were observed for rs4986938. In conditional logistic multivariate regression, the rs1271572 variant was associated with increased odds of CVD [odds ratio (OR) = 1.49, 95% CI: 1.10-2.01] and MI (OR = 1.46, 95% CI: 0.96-2.23), whereas the rs1256049 variant was associated with decreased odds of CVD (OR = 0.37, 95% CI: 0.17-0.79) and MI (OR = 0.25, 95% CI: 0.09-0.73) in women. A common haplotype that included the rs1271572 variant was associated with a 7-fold increased risk of MI in women. CONCLUSIONS: Two tightly linked polymorphisms of ESR2 were associated with risk of CVD, particularly MI, in women but not men. Additional studies of ESR2 genetic variation and risk of CVD are warranted.     

Hormone replacement therapy and the risk of venous thromboembolism: a population‐based study

Summary. Background: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. Methods: Among the United Kingdom’s General Practice Research Database, we identified the cohort of all women aged 50–79 between 1 January 1987 and 1 March 2008. Using a nested case–control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. Results: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89–1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77–1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77–1.10), relative to non‐use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37–1.63) and oral estrogen–progestogen (RR 1.54; 95% CI, 1.44–1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. Conclusion: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.     

Association of Early versus Late Initiation of Dialysis with Mortality: Systematic Review and Meta-Analysis

Background/Aims: The association of the timing of dialysis initiation with mortality is controversial. We conducted a meta-analysis to determine the relationship between the risk of death and early initiation of dialysis, when the patient has a greater estimated glomerular filtration rate (eGFR). Methods: Prospective and retrospective cohort studies that independently measured the effect of early vs. late initiation of dialysis on risk of death were identified by review of several databases. Odds ratios (ORs) were estimated by comparison of the highest and lowest quartiles and combined by a random-effects model. Results: 15 studies (1,285,747 patients) met the inclusion criteria. Summary estimates indicated that early start of dialysis was associated with increased risk of mortality (OR = 1.33, 95% confidence interval (CI): 1.18-1.49, p < 0.00001). Subgroup analysis indicated that early starters were 6.61 years older (p < 0.00001) and more likely to have diabetes (OR = 2.23, 95% CI: 1.83-2.71, p < 0.00001) than late starters. Analysis of pooled results of early and late starters indicated that older age (OR = 1.18, 95% CI: 1.05-1.33, p = 0.006), diabetes (OR = 1.61, 95% CI: 1.38-1.87, p < 0.00001), and high comorbidity index score (OR = 2.38, 95% CI: 1.75-3.25, p < 0.00001) were strongly associated with increased risk of death. Conclusion: Our meta-analysis indicates that early initiation of dialysis (at higher eGFR) was associated with an increased risk of death. Older age, greater likelihood of diabetes, and the presence of severe comorbid disease(s) partly explain this effect.     

High risk of recurrent venous thromboembolism in men

BACKGROUND: We have analyzed the influence of gender on risk of recurrence after a first episode of venous thromboembolism (VTE). METHODS: The Cambridge Venous Thromboembolism Study (CVTE) is a single-center study of a cohort of unselected patients with a first episode of objectively proven VTE. RESULTS: Recurrence rates were significantly higher in men compared with women [log rank chi2=11.82; hazard ratio (HR) 2.66; 95% confidence interval (CI) 1.49, 4,77; P=0.0006]. The cumulative recurrence rate at 2 years was 19.2% in men and 7.7% in women. There was no evidence of a difference in recurrence between men with or without thrombophilia (log rank chi2=0.03; HR 1.08; 95% CI 0.49, 2.37; P=0.855). The high recurrence rate in men compared with women was still observed when only patients with idiopathic VTE were analyzed (log rank chi2=4.38; HR 2.31; 95% CI 1.027, 5.20; P=0.0363). The recurrence risk was highest in men with a first idiopathic event at 25.7% compared with 11.7% for women in the same category. CONCLUSION: The risk of recurrent VTE is higher in men than in women.     

High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses

BACKGROUND: Diabetes mellitus is generally not recognized as an important risk factor for venous thromboembolism (VTE). However, clinical observations and case reports have suggested that patients with diabetes and hyperosmolarity may be at increased risk for VTE. Objectives: To determine the risk of VTE in patients hospitalized for diabetes with hyperosmolar state compared to patients with other acute medical illnesses. PATIENTS/METHODS: The California Patient Discharge Data Set was used to determine the incidence of first-time VTE in all patients admitted between 1995 and 2000 for diabetes with hyperosmolarity and 11 other acute medical conditions. Proportional hazard modeling was used to adjust for age, race, gender, and prior hospitalization within 3 months. RESULTS: Among 2859 patients with diabetes and hyperosmolarity, 34 (1.2%) developed VTE during the hospitalization and 14 (0.5%) developed VTE within 91 days after discharge. In an adjusted multivariate model comparing the risk of VTE to cases with depression, patients with hyperosmolarity had a significantly higher risk of VTE [hazard ratio (HR) = 16.3; 95% confidence interval (CI): 10-25] comparable to the risk associated with sepsis (HR = 19.3; 95% CI: 13-29) or acute connective tissue disease (HR = 21; 95% CI: 15-31). Compared to uncomplicated diabetes, patients with hyperosmolarity had a significantly higher risk of VTE (HR = 3.0; 95% CI: 2.1-4.5) whereas patients with ketoacidosis were not at higher risk (HR = 1.2; 95% CI: 0.8-1.7). CONCLUSIONS: Patients hospitalized for diabetes with hyperosmolarity are at increased risk for developing VTE both during their inpatient stay and in the 3 months after discharge. Thromboprophylaxis in these patients appears warranted, and extended prophylaxis for after hospital discharge should be studied.     

Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. OBJECTIVE: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. RESULTS: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). CONCLUSIONS: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.     

Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemia

BACKGROUND: In the present study we assessed whether the presence of genetic mutations typical of familial hypercholesterolaemia (FH) was associated with greater atherosclerosis in the coronary vessels in patients with severe hypercholesterolaemia and a family history of early cardiovascular disease. MATERIALS AND METHODS: Two hundred and thirty-five patients selected for having severe hypercholesterolaemia and a family history of cardiovascular disease were classified as FH (57 men and 38 women) or non-FH (84 men and 56 women) according to a genetic analysis of the LDL-R or ApoB genes. Coronary atherosclerosis was evaluated by performing a thoracic CT scan and exercise stress testing. RESULTS: Familial hypercholesterolaemia individuals had a significantly higher prevalence of coronary calcification than the non-FH patients from among both the men (OR = 3.90; 95% CI 1.86-8.19; P < 0.001) and the women (OR = 2.34; 95% CI 1.01-5.48; P = 0.05). In exercise stress testing, ECG abnormalities suggestive of cardiac ischaemia were found with a higher prevalence in the FH patients than the non-FH patients from among both the men (OR 6.15; 95% CI 2.16-17.5; P < 0.001) and the women (OR 4.76; 95% CI 0.91-24.6; P = 0.06). All differences were statistically significant after adjusting for age and cholesterol and for most classical risk factors that differed between the FH and non-FH groups. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher prevalence of coronary artery calcifications and a positive exercise stress test. These results suggest that despite a similar phenotype, patients carrying mutations suggestive of FH may have a greater cardiovascular risk than patients without these mutations.     

Miscarriage after a normal scan at 12-14 gestational weeks in women at low risk of carrying a fetus with chromosomal anomaly according to nuchal translucency screening.

OBJECTIVES: To estimate the risk of second-trimester miscarriage in women with low risk of carrying a fetus with chromosomal abnormality, according to nuchal translucency (NT) screening, and to determine whether NT thickness or other factors affect the risk. METHODS: The study population comprised 14 278 singleton pregnancies with a risk of Down syndrome < 1:250 at NT scan, and where no fetal karyotyping was performed < 25 weeks. Risk factors for miscarriage were investigated by logistic regression. RESULTS: The median risk of Down syndrome was 1 : 3138 (range 1 : 9651-1 : 251) and median NT was 1.7 (range 0.4-3.0) mm. The miscarriage rate was 0.5% (77/14 278; 95% CI 0.4-0.6). After having controlled for maternal age, we found the number of previous deliveries and miscarriages to independently predict miscarriage: odds ratio (OR) for each previous delivery 1.48, 95% CI 1.22-1.94, P < 0.0001; OR for each previous miscarriage 1.34, 95% CI 1.07-1.68, P = 0.01. Excluding women with any previous miscarriage and adjusting for parity, we found a U-shaped relationship between maternal age and miscarriage (P = 0.04). CONCLUSION: In singleton pregnancies with estimated risk of Down syndrome < 1:250 according to NT screening at 12-14 weeks, the spontaneous fetal loss rate before 25 weeks is likely to be around 0.5%. NT thickness up to 3 mm does not seem to affect the risk of miscarriage in such pregnancies. Instead, the risk seems to increase with number of previous miscarriages and deliveries, and possibly the risk is highest in the youngest and oldest women.     

Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group

OBJECTIVE: To evaluate whether the increased risk of type 1 diabetes conferred by an early introduction of cow's milk supplements can be mediated by accelerated growth in formula-fed infants. RESEARCH DESIGN AND METHODS: All children < or = 14 years of age who were diagnosed with type 1 diabetes from September 1986 to April 1989 were invited to participate in the study. Birth date- and sex-matched control children were randomly selected from the Finnish Population Registry. At least three weight measurements from the first year of life were obtained for 435 full-term diabetic subjects and 386 control subjects from well-baby clinics and school health care units. RESULTS: Increase in body weight was greater in the diabetic girls than in the control girls, and the difference increased from 111 g (95% CI 0-218, P = 0.04) at 1 month of age to 286 g (95% CI 123-450, P = 0.0006) at 7 months. For boys, the difference in weight between the diabetic subjects and the control subjects remained stable during infancy (difference 95 g, 95% CI-2-205, P = 0.09). Increased weight was associated on average with a 1.5-fold risk of type 1 diabetes. Early introduction of formula feeding (< 3 vs. > or = 3 months) was also associated with an increased risk of type 1 diabetes after adjustment for the individual weight gain curve (adjusted odds ratio 1.53, 95% CI 1.1-2.2). No evidence for interaction was observed. CONCLUSIONS: These observations indicate that an early exposure to cow's milk formula-feeding and rapid growth in infancy are independent risk factors of childhood type 1 diabetes.