Marc Blondon

Fibroblast Growth Factor-23 and Cardiovascular Disease in the General Population: The Multi-Ethnic Study of Atherosclerosis

Background—Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort. Methods and Results—We evaluated 6547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular mass by MRI, coronary calcium by computed tomography, and carotid intima-media thickness by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stroke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4-g greater left ventricular mass (95% confidence interval, 0.4–4.5 greater) and a 26% greater odds of higher coronary calcium scores (95% confidence interval, 9%–46% greater) compared with the lowest quartile. During 7.5-year follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% confidence interval, 3%–37% greater) and a 14% greater risk of coronary heart disease (95% confidence interval, 1%–28% greater). FGF-23 was not associated with carotid intima-media thickness or stroke. Conclusions—Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid intima-media thickness or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.

Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens

IMPORTANCE Little is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat menopausal symptoms. OBJECTIVE To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs-conjugated equine estrogens (CEEs) and estradiol. DESIGN, SETTING, AND PARTICIPANTS Population-based, case-control study from January 1, 2003, to December 31, 2009, comparing cardiovascular event risk associated with current CEEs and estradiol use in a large health maintenance organization in which the preferred formulary estrogen changed from CEEs to estradiol during the course of data collection. Participants were 384 postmenopausal women aged 30 to 79 years using oral hormone therapy. MAIN OUTCOMES AND MEASURES Incident venous thrombosis was the primary clinical outcome, and incident myocardial infarction and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, the endogenous thrombin potential-based normalized activated protein C sensitivity ratio, was measured in plasma of controls. RESULTS We studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02-4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91-3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55-2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential-based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity. CONCLUSIONS AND RELEVANCE In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.

25-Hydroxyvitamin D and Parathyroid Hormone Are Not Associated With Carotid Intima-Media Thickness or Plaque in the Multi-Ethnic Study of Atherosclerosis

Objective—Observational evidence supports independent associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) with cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis. Approach and Results—We evaluated cross-sectional and longitudinal associations of 25-OHD and PTH with carotid intima-media thickness (IMT) and carotid plaques among 3251 participants free of cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. 25-OHD and PTH were measured at baseline by mass spectrometry and immunoassay, respectively. All subjects underwent a carotid ultrasound examination at baseline and 9.4 years later (median, range 8–11.1 years). Multivariable linear and logistic regressions were used to test associations of 25-OHD and PTH with the extent and progression of IMT and the prevalence and incidence of carotid plaque. Mean (SD) 25-OHD and PTH were 25.8 ng/mL (10.6) and 44.2 pg/mL (20.2), respectively. No independent associations were found between 25-OHD or PTH and IMT at baseline (increment of 1.9 &mgr;m [95% confidence interval, −5.1 to 8.9] per 10 ng/mL lower 25-OHD; increment of 0.8 &mgr;m [95% confidence interval, −3.2 to 4.8] per 10 pg/mL higher PTH) or progression of IMT (increment of 2.6 &mgr;m [95% confidence interval, −2.5 to 7.8] per 10 ng/mL lower 25-OHD, increment of 1.6 &;m [95% confidence interval, −1.9 to 5.2] per 10 pg/mL higher PTH). No associations were found with the baseline prevalence of carotid plaque or the incidence of new plaques during the study period. We did not observe any interaction by race or ethnicity (White, Chinese, Black, and Hispanic). Conclusions—The consistent lack of association of vitamin D and PTH with carotid IMT and plaque suggests that these hormones may influence cardiovascular risk through pathways not reflected by carotid atherosclerosis.

Natural history of patients with congenital dysfibrinogenemia

We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event.

Fondaparinux for Isolated Superficial Vein Thrombosis of the Legs: A Cost-Effectiveness Analysis

BACKGROUND According to the Comparison of Arixtra in Lower Limb Superficial Vein Thrombosis with Placebo (CALISTO) study, a recent randomized, controlled trial, prophylactic fondaparinux can prevent thrombotic complications following superficial vein thrombosis (SVT). The cost-effectiveness of this treatment remains to be determined. METHODS We developed a decision-tree model comparing fondaparinux 2.5 mg daily for 45 days vs no treatment of SVT. It included all clinical events associated with SVT, its treatment, its complications, and all respective quality-adjustment factors. Data were mainly derived from the CALISTO study and the published literature. Measured outcomes comprised clinical events (VTE, major hemorrhage, death), quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). The analysis was conducted using a lifetime time horizon from a health-care system perspective. We performed one-way and probabilistic sensitivity analyses to evaluate parameter uncertainty. RESULTS In 10,000 patients, we estimated that fondaparinux would prevent 123 VTE events and two deaths. On a per-patient basis, the incremental QALY compared with no treatment was 0.04 (1 day) at an incremental cost of

Thromboprophylaxis with low-molecular-weight heparin after cesarean delivery

1,734, resulting in an ICER of

Predicting deep venous thrombosis in pregnancy: external validation of the LEFT clinical prediction rule

500,000 per QALY. This result remained robust in the one-way sensitivity analyses, with an ICER remaining >

The association of smoking with venous thrombosis in women. A population-based, case-control study

100,000 per QALY throughout all ranges. Based on probabilistic sensitivity analyses, the probability that fondaparinux was cost-effective was 1% at a willingness-to-pay of

25-Hydroxyvitamin D and Parathyroid Hormone Levels Do Not Predict Changes in Carotid Arterial Stiffness The Multi-Ethnic Study of Atherosclerosis

100,000 per QALY. CONCLUSIONS Fondaparinux for 45 days does not appear to be cost-effective when treating patients with isolated SVT of the legs. A better value for money could be obtained in subgroups of patients with a higher incidence of VTE after SVT. Shorter durations of treatment should be further evaluated in future clinical studies.

Validation of methods for assessing cardiovascular disease using electronic health data in a cohort of Veterans with diabetes.

Although venous thromboembolism (VTE) is the leading cause of maternal mortality in developed countries, the usefulness of preventive low-molecular-weight heparin (LMWH) after cesarean delivery remains a matter of controversy. It was the objective of this study to evaluate the usefulness of thromboprophylaxis with LMWH after cesarean delivery. A decision model was constructed to evaluate the risks and benefits associated with a seven-day LMWH prophylaxis, compared with none. All probabilities were obtained from literature according to the highest level of evidence. We performed our analysis on two different sets of outcomes (utilities and disutilities), to calculate the quality-adjusted life expectancy at three months. Finally, we calculated the outcomes for four hypothetical cases with different risk. Prophylaxis with LMWH yielded the highest quality-adjusted life expectancy, with a net gain of 1.5-2.8 quality-adjusted days. Sensitivity analyses showed the incidence of VTE after cesarean delivery and the haemorrhagic risk related to LMWH to be critical, at threshold values of 0.15-0.22% and 0.23-0.35%, respectively. In the hypothetical cases, LMWH was safe but only marginally more effective in women with no risk factors. In case of an emergency procedure, a body-mass index >25kg/m(2), tobacco smoking, or any combination of these, reductions in VTE greatly outnumbered the increase in major haemorrhages, with a modest benefit on mortality. Our decision analysis suggests that the benefits of LMWH after cesarean delivery exceed the risks. This benefit is, however, very low in women with no risk factors.