Increase In Venous Thromboembolic Events Research Articles

Cardiometabolic Effects of Endocrine Treatment of Estrogen Receptor-Positive Early Breast Cancer.

Estrogen receptor–positive early breast cancer is common and has a relatively good prognosis. It shares risk factors with cardiovascular disease, and cardiovascular disease is an important competing cause of mortality. Adjuvant endocrine therapy with aromatase inhibitors (requiring concomitant ovarian suppression in premenopausal women) or selective estrogen receptor modulators (usually tamoxifen) exert oncologic benefits by respectively inhibiting estradiol synthesis or breast estrogen receptor signaling. Aromatase inhibitors cause systemic estradiol depletion. Tamoxifen has mixed agonistic/antagonistic effects in a tissue-dependent fashion. Given that estrogens modulate cardiometabolic risk, a review of the effects of endocrine therapy on cardiometabolic outcomes is pertinent. The current, but limited, evidence suggests that tamoxifen treatment, although associated with increases in body fat, hepatic steatosis, serum triglycerides, and diabetes risk, modestly reduces low-density lipoprotein cholesterol and lipoprotein(a) and may have favorable effects on markers of subclinical atherosclerosis. Tamoxifen is associated with either no effect on, or a reduction in, cardiovascular events, and it is associated with an increase in venous thromboembolic events. Aromatase inhibitors, although fewer studies are available and often confounded by comparison with tamoxifen, have not been consistently associated with adverse changes in cardiometabolic risk factors or increases in cardiovascular events. Further clinical trials designed to evaluate cardiometabolic outcomes are needed to more accurately determine the effects of endocrine therapy on cardiovascular risks, to inform individualized decisions regarding choice and duration of endocrine therapy, and to implement evidence-based strategies to mitigate cardiometabolic risks. In the meantime, although breast cancer–specific evidence for benefit of lifestyle measures is available and recommended routinely, proactive monitoring and treatment of cardiovascular risk factors should follow general population recommendations.

OP0200 Thromboembolism in Rheumatology: Investigation of the Risks of Deep Vein Thrombosis and Pulmonary Embolism in Inflammatory Arthritis, Connective Tissue Diseases, Vasculitis and Myositis

BackgroundWe performed a meta-analysis investigating the risk of developing deep vein thrombosis (DVT) and/or pulmonary embolisms (PE) in patients with inflammatory arthritis, vasculitis, and connective tissue diseases (CTD) [SLE, Sjogren's...

Risk of deep vein thrombosis and pulmonary embolism in asthma

Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age- and sex-matched reference population. 648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified. In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20-63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42-1.44) per 1000 person-years, 0.33 (95% CI 0.07-0.60) in mild-to-moderate asthma and 0.18 (95% CI 0.03-0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16-9.93) and 2.82 (1.09-7.30), respectively). Asthma was not associated with deep vein thrombosis. Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used.

Noncardiac vascular disease in rheumatoid arthritis: Increase in venous thromboembolic events?

To investigate the incidence of noncardiac vascular disease in a community-based incidence cohort of patients with rheumatoid arthritis (RA) and compare it to that in the general population and to investigate trends in the incidence of noncardiac vascular disease in patients with RA. A population-based inception cohort of patients with incident RA between January 1, 1980 and December 31, 2007 in Olmsted County, Minnesota and a cohort of non-RA subjects from the same population base was assembled and followed up until December 31, 2008. Venous thromboembolic, cerebrovascular, and peripheral arterial events were ascertained by medical record review. The study population included 813 patients with RA with a mean±SD age of 55.9±15.7 years (68% women) and an average length of followup of 9.6±6.9 years. Compared to non-RA subjects of similar age and sex, patients diagnosed as having RA between 1995 and 2007 had a higher incidence (%) of venous thromboembolism (cumulative incidence±SE 6.7±1.7 versus 2.8±1.1, respectively; P=0.005) but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of venous thromboembolic, cerebrovascular, and peripheral arterial events was similar in the 1995-2007 time period compared to the 1980-1994 time period. Our findings indicate that the incidence of venous thromboembolism is increased in patients with RA compared to non-RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events is similar in patients with RA compared to non-RA subjects. Among patients with RA, the incidence of noncardiac vascular disease has remained stable in recent decades.

Toremifene Decreases Vertebral Fractures in Men Younger Than 80 Years Receiving Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy is associated with an increased fracture risk. In a recent phase III trial toremifene significantly decreased vertebral fractures in men on androgen deprivation therapy. Similar to other selective estrogen receptor modulators, toremifene was associated with an increase in venous thromboembolic events with the greatest risk in men 80 years old or older. In this post hoc analysis we evaluated the efficacy and safety of toremifene in men younger than 80 years. This analysis included 847 men younger than 80 years, of whom 430 received toremifene 80 mg by mouth daily and 417 received placebo for up to 24 months. The primary end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and safety. Compared with placebo, toremifene decreased the relative risk of new vertebral fractures by 79.5% (95% CI 29.8-94.0, p <0.005). The new vertebral fracture incidence was 1.0% for toremifene and 4.8% for placebo (absolute risk reduction 3.8%). Compared with placebo, toremifene significantly decreased the incidence of nontraumatic fracture or greater than 7% bone loss by 24 months (p <0.0001). Toremifene also significantly increased bone mineral density at all measured sites (all comparisons p <0.001). The incidence of venous thromboembolic events was similar in the toremifene and placebo groups (2.1% and 1.0%, respectively, p = 0.26). The rates of other adverse events were also similar between the groups. Toremifene significantly decreased new vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer. The risk of venous thromboembolic events was lower than in the overall study population, suggesting an improved risk-benefit profile in younger men.

Effect of toremifene on fracture risk in men younger than age 80 on androgen-deprivation therapy.

4676 Background: The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events. This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years. Methods: In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 men received toremifene 80 mg and 417 received placebo (orally daily). All subjects were on ADT for ≥ 6 months, had a serum PSA ≤4 ng/mL, were ≥70 years of age or were at or below WHO thresholds for spine or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures and bone mineral density (BMD). Results: Toremifene 80 mg demonstrated a 79.5% relative risk reduction in the incidence of new vertebral fractures (CI0.95: 29.8%-94.0%; p<0.005). The absolute reduction was 3.8% (4.8% placebo, 1.0% toremifene). Toremifene 80 mg significantly increased BMD at all sites measured (p<0.001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p<0.001 for all comparisons). Venous thromboembolic events occurred in 2.1% of the toremifene patients compared to 1.0% (p=0.26) of the placebo patients. Other adverse events were similar between groups. Conclusions: In men <80 years receiving ADT for prostate cancer, toremifene significantly decreased the incidence of new vertebral fractures. Toremifene also significantly improved BMD, bone turnover markers, and breast pain and tenderness. The risk of VTE was lower than in the overall study population. These results suggest an improved benefit/risk profile in men <80 years receiving ADT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GTx Amgen, GTx, Novartis GTx Amgen, GTx, Novartis GTx

Lasofoxifene in Postmenopausal Women with Osteoporosis

The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

An Expanded Post-Thrombosis Sequelae Assessment Scale in Children.

OBJECTIVE: The prevalence of post-thrombosis sequelae (PTS) is increasing in children due to an increase in venous thromboembolic events (VTEs). Pediatric PTS involves extremity and non-extremity manifestations depending on the location of VTEs. Existent PTS assessment scales assess the severity of extremity PTS only. The aim of this study was to develop a clinically significant Expanded PTS Assessment Scale (EPTSAS) which will incorporate both extremity and non-extremity manifestations and provide a framework for interventions.METHOD: All children with objectively confirmed VTEs that were prospectively followed in the Pediatric Coagulation clinic from 2004 to 2006 were included in the study. The clinical consequences that could be directly attributed to intravenous hypertension due to VTEs were carefully recorded and an EPTSAS was developed. This scale included 4 major (varicosities, ulceration, non-extremity manifestations, radiological findings) and 9 minor criteria (pain, swelling, venous collaterals, limb-length and limb-circumference discrepancies, facial swelling, increase in head circumference, activity limitation, tenderness, skin hyperpigmentation). The interpretation was categorized into 3 grades: clinically non-significant, clinically significant and clinically severe (Table). Three independent investigators classified the patients using EPTSAS, one of whom was a pediatric hematologist whose responses were considered gold standard. The clinical diagnosis of PTS was reinforced by an observed response to treatment and decrease in PTS score on follow up visits.RESULTS: Fifty children were eligible for assessment. Median age at diagnosis of PTS: 4.6 years (90 days to 22 years). Median follow up: 1 year (180 days to 10 years). Median interval between diagnosis of VTE and development of PTS:180 days (90 to 3 years). Anatomical locations of VTEs were as follows: lower extremity,23; upper extremity,12; intrathoracic,4; intra-abdominal,3; head and neck,8 (neck:3, sinovenous thrombosis:5); multiple locations,5. Frequently observed symptoms were: collaterals 20/50(40%), swelling 13/50(26%), pain 7/50(14%) and activity limitation 10/50(20%). Six(12%) children developed non-extremity manifestations as a consequence of regional thrombosis: portal hypertension,3; chylothorax,1, communicating hydrocephalus, 1; loss of kidney,1. Twenty-seven (54%) children received a score ≥1 on either a major or minor criteria. Based on EPTSAS aggregate scores, PTS were classified as: clinically non-significant:8/27(30%); clinically significant:6/27(22%), clinically severe:13/27(48%). Three of 6 with non-extremity PTS were missed by existing PTS scales. The positive predictive value, negative predicitve value, sensitivity and specifity of EPTSAS at 1 year after initial assessment was 75%(15/20), 100%(30/30),100%(15/15) and 86%(30/35) respectivley. Inter-observer agreement was good, 78%. Intra-observer agreement was very good, 90%.CONCLUSIONS: This study shows that EPTSAS allows the evaluation of PTS to better cover the full scope of venous thrombotic complications in children. The validity of this EPTSAS will be evaluated prospectively with a larger sample size.Expanded Post-Thrombosis Sequelae Assessment ScaleScoreInterpretationManagementMajor 0 + Minor <4Clinically non-significantNo interventionMajor 0 + Minor ≥4 or Major 1 + Minor 2 or Major 2 + Minor 0Clinically significantClose observation± interventionMajor 1 + Minor ≥3 or Major ≥2+ Minor ≥1Clinically severeImmediate intervention