Elevated Risk Of Venous Thromboembolism Research Articles

Controversies in postpartum contraception: When is it safe to start oral contraceptives after childbirth?

The timely initiation of contraception postpartum is an important consideration for breastfeeding and non-breastfeeding women; many women prefer oral contraceptive pills to other methods. In breastfeeding women, combined hormonal pills are not recommended prior to 6 weeks postpartum, due to effects on milk production. Although progestogen-only pills do not adversely affect milk, lack of data regarding possible effects on infants exposed to progestogens in breastmilk renders timing of initiation of this method controversial. In non-breastfeeding women, elevated risk of venous thromboembolism restricts use of combined hormonal pills prior to 21 days postpartum. From 21 to 42 days, use of combined hormonal pills should be assessed based on a woman's personal venous thromboembolism risk profile; after 42 days postpartum there is no restriction in the use of combined hormonal pills for otherwise healthy women. Non-breastfeeding women may safely use progestogen-only pills at any time during the postpartum.

Venous Thromboembolic Disease in Congestive Heart Failure

Congestive heart failure (CHF) is a medical condition associated with a relatively high risk of venous thromboembolism (VTE). Without thromboprophylaxis, venographically proven deep vein thrombosis occurs in 10% to 22% of hospitalized patients with CHF. Although the elevated VTE risk associated with CHF has been attributed to a variety of abnormalities in the context of Virchow's triad, newer information suggests that an associated chronic inflammatory state may be culpable. Both traditional VTE risk factors and cardiac-specific risk factors further increase the risk of VTE in patients with CHF. Severe left ventricular dysfunction, clinical instability (New York Heart Association class III-IV), young age, and/or right ventricular dysfunction appear to enhance the VTE risk associated with CHF. Grade IA pharmacologic thromboprophylactic recommendations for the hospitalized CHF patient include low molecular weight-heparin, fondaparinux, and low-dose unfractionated heparin. Regrettably, a variance in societal guidelines on the importance of VTE in hospitalized CHF patients may lead to underutilization of thromboprophylaxis.

S1207 Elevated Risk of Venous Thromboembolism in Patients With Inflammatory Bowel Disease: Results From a European Population-Based Cohort

S1207 Elevated Risk of Venous Thromboembolism in Patients With Inflammatory Bowel Disease: Results From a European Population-Based Cohort

Antithrombotic therapy and survival in patients with malignant disease

A broad range of studies suggest a two-way relationship between cancer and venous thromboembolism (VTE). Patients with cancer have consistently been shown to be at elevated risk for VTE; this risk is partly driven by an intrinsic hypercoagulable state elicited by the tumour itself. Conversely, thromboembolic events in patients without obvious risk factors are often the first clinical manifestation of an undiagnosed malignancy. The relationship between VTE and cancer is further supported by a number of trials and meta-analyses which, when taken together, strongly suggest that antithrombotic therapy can extend survival in patients with cancer by a mechanism that extends beyond its effect in preventing VTE. Moreover, accumulating evidence from in vitro and in vivo studies has shown that tumour growth, invasion, and metastasis are governed, in part, by elements of the coagulation system. On 22 May 2009, a group of health-care providers based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees evaluated evidence for and against an effect of antithrombotic therapy on survival in cancer. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents might exert antitumour effects. The summary is followed by a consensus statement developed by the group.

Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens.

Abstract 1873Poster Board I-898Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep-vein thrombosis (DVT) and pulmonary embolism (PE). The VTE risk in MM is increased by various patient- and disease-related factors; however, type of anti-MM therapy represents a key factor, with a substantially elevated risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide (thal) or lenalidomide (len) in combination with dexamethasone (dex) and/or chemotherapy (Palumbo et al, Leukemia 2008); VTE risk with len-dex (RD) is further increased with concomitant erythropoietin (EPO). By contrast, treatment with the proteasome inhibitor bortezomib (btz), either alone or in combination, does not increase VTE risk. In the VISTA phase 3 trial of melphalan-prednisone (MP) vs btz plus MP (VMP) in previously untreated MM patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008), data from an updated safety analysis showed similar rates of DVT (VMP: 5/340 [1%], four grade 3; MP: 6/337 [2%], two grade 3) and PE (VMP: 4/340 [1%], two grade 4; MP: 3/337 [1%], one grade 3, two grade 4) between arms; as reported by Richardson et al (IMW 2009), rates of DVT/PE were not affected by use of erythropoiesis-stimulating agents, including EPO. These findings reflect those from the APEX phase 3 trial of single-agent btz vs high-dose dex in relapsed MM (Lonial et al, Br J Haematol 2008); rates of DVT/PE were low (0.6% vs 2.7%) and unaffected by concomitant EPO use, and VTE risk appeared lower with btz vs dex, controlling for EPO use (odds ratio 0.207, p=0.046). As previously reported, btz shows anti-hemostatic effects in patients with relapsed or refractory MM, resulting in a decrease in platelet count and significant reductions in agonist-induced platelet aggregation (Zangari et al, Haematologica 2008); these findings support btz exerting anti-thrombotic actions and thus potentially providing a protective effect in combination with regimens with elevated VTE risk. A review of data from phase 3 trials of btz- and/or IMiD-based therapy in frontline MM and other studies of novel combination regimens supports this hypothesis. Despite the confounding effect of variable VTE prophylaxis, btz-based regimens are associated with DVT/PE rates of 0–4% (Figure), similar to those seen with MP and dex alone (Palumbo et al, Leukemia 2008), whereas IMiD-based btz-free regimens are generally associated with substantially higher rates. Direct comparisons of regimens of thrombogenic potential with/without btz demonstrate lower VTE risk with btz; as previously reported, DVT rates of 0% vs 10% (p=0.0006) were seen with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) with vs without btz in an analysis of patients enrolled on two University of Arkansas trials (Zangari et al, ASH 2004). Palumbo et al (EHA 2009) also reported lower rates of VTE events with btz, thal, dex (VTD, ∼4.5%) and VMP—thal (VMPT, ∼2.7%) vs TD (7%) in a phase 3 randomized trial of aspirin, low molecular weight heparin, and warfarin as VTE prophylaxis, while in another phase 3 study Rosiñol et al (ASH 2008) showed a lower rate of thrombotic events with VTD vs TD (1.7% vs 13%, p=0.02, no prophylaxis). Indirect, between-study comparisons of VTE risk support these findings; in six phase 3 studies, TD was associated with 5.5–23% DVT/PE, while in two phase 3 studies, the rate with VTD was 1.7–4%. Similarly, rates were 6–12% in five phase 3 studies of MP-thal (MPT) vs 4% with VMPT (Palumbo et al, EHA 2009). Finally, len-low-dose dex (Rd) and RD resulted in DVT/PE rates of 12–27% in two phase 3 studies, whereas a rate of only 4% was reported in a phase 1/2 study of btz-RD (RVD) by Richardson et al (IMW 2009). Taken together, these findings confirm the low VTE risk associated with btz and support a potential protective effect of btz in combination with IMiD-based regimens associated with elevated VTE risk. [Display omitted] Disclosures:Zangari:Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Fink:DOD Radioprotectants: Research Funding.

Circulating tumor cells and risk of venous thromboembolism in metastatic breast cancer patients

1060 Background: Cancer is well-recognized risk factor for venous thromboembolism (VTE), and VTE is associated with a higher risk of death in cancer patients. Coagulation activation by tissue factor (TF) is associated with cancer growth and disease progression. Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. The aim of this study was to test the hypothesis that CTCs are associated with the risk of VTE in MBC patients. Methods: This retrospective study included 362 MBC patients treated in M. D. Anderson Cancer Center between January 2004 and December 2007. CTCs were detected and enumerated using the CellSearch system. Patients were assigned to cohorts based on the highest CTC counts during the course of the disease. All venous thrombosis and/or pulmonary embolism in the presence of unequivocal medical documentation were classified as events. Results: At a median follow up of 11.1 months (range 0–38 months) 30 patients (8.3%) experienced VTE. Median survival was 16.3 months vs. 37.2 months (p = 0.003) in patients with and without VTE, respectively. Patients with ≥ 3 CTCs had an elevated risk of VTE in comparison to patients with < 3 CTCs (12.1% vs 3.7%; p = 0.003). In multivariate analysis, the presence of visceral metastasis, increased number of metastatic sites and ≥ 3 CTCs were associated with the risk of VTE. Conclusions: This retrospective study showed that CTCs are associated with increased risk of VTE in MBC. Prospective assessment of coagulation status and its correlation to CTC counts and clinical outcome are warranted. No significant financial relationships to disclose.

Antipsychotics and risk of venous thromboembolism: A population-based case-control study

During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997-2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91-180 days), former (at least one prescription within 181-365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69-2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99-2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding.

Patterns of Venous Thromboembolism (VTE) Following Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM) among 4 Million U.S. Veterans.

Background: VTE risk in MM patients has been reported to be 5 to 50-fold higher than the crude population incidence of 0.5 per 1000 person-years. The introduction of oral immunomodulatory drugs (e.g. thalidomide and lenalidomide) has contributed substantially to the increased risk of VTE in MM, however the precise contribution of host and drug related mechanisms remain unclear. Recently, 2 small studies reported that MGUS is associated with an elevated VTE risk suggesting that VTE might be an early marker for MM transformation in MGUS patients.Objective: To define patterns of VTE following MGUS and MM among adult male U.S. Veterans.Patients and Methods: The cohort was identified from review of discharge diagnoses in hospital medical records for inpatient hospitalizations at 142 nationwide U.S. Veterans Affairs (VA) hospitals between October 1, 1980 and September 30, 1996. The target population for VTE incidence calculation included all (N=4,201,697) male veterans hospitalized at least once at age 18 or older who survived one year after index hospital visit. Mean follow-up was 10 years. For estimating the risk of VTE following MGUS and MM, all MGUS and MM patients were followed until the diagnosis of a first VTE, a MM diagnosis for MGUS cases, death, or the end of the observation period, whichever came first. The estimated cumulative probability and 95% confidence intervals of developing VTE among MGUS and MM cases used Kaplan-Meier methods.Results: We identified 22,781 VTE events in the entire VA population (crude incidence: 0.5 per 1000 person-years). Among 2424 MGUS and 6282 MM patients, 18 (1.7 per 1000 person-years) and 83 (4.2 per 1000 person-years) developed VTE, respectively. The estimated cumulative risk of developing VTE 4 years after MGUS/MM was significantly lower for patients with MGUS (0.47%; 0.15%–0.78%) versus MM (1.80%; 1.37%–2.22%). After 5 years of follow-up the relative risk of VTE following MGUS (vs. MM) increased significantly and 8 years after MGUS/MM diagnosis the cumulative VTE risk was very similar for patients with MGUS (1.91%; 0.84%–2.96%) and MM (2.23%; 1.62%–2.83%). Among MGUS patients there were 229 (9.4%) who progressed to MM; only 1 of these patients developed VTE prior MM.Conclusions: The crude incidence of VTE among U.S. Veterans was similar to that reported in prior population-based studies. We found 4-fold and 8-fold elevated crude VTE incidence among MGUS and MM patients, respectively. MGUS patients had a low cumulative VTE risk during the first years of follow-up but over time approached that of MM. The VTE risk in MGUS patients rose significantly after 5 years of follow-up and at 8 years of follow-up the cumulative VTE risk was similar for MGUS and MM. These results suggest there are underlying gradually progressing pathogenetic mechanisms in MGUS reflected in increased hypercoagulation, e.g. increased angiogenesis, elevated IL-6 and TNF secretion, and acquired cytogenetic lesions such as (11;14) translocations. Interestingly, chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus have been proposed as early events in the development of both MGUS and MM. However, we found no evidence for VTE being associated with MM transformation in MGUS.

The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits – an attempt to interpret the Women's Health Initiative results

The results of the two arms of the Women's Health Initiative (WHI) study allow a comparative assessment of the contribution of the progestogen component to the changes in risk of cardiovascular disease and cancer during treatment of postmenopausal women with conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). However, the high proportion of older and overweight or obese women compromises any conclusions, since we estimate that 50% of the women would have the metabolic syndrome. In overweight postmenopausal women with hyperinsulinemia, the risk of breast cancer is elevated and cannot be increased further by hormone replacement therapy (HRT). Therefore, the non-significant, but consistent reduction in breast cancer risk during treatment with CEE alone might be based on an improvement of hyperinsulinemia. The 24% increase in breast cancer risk in the CEE/MPA group can be regarded as an artifact due to very low numbers of breast cancer diagnoses in the placebo group of women who had received HRT prior to the WHI study. The elevated risk of venous thromboembolism and the transient increase in the risk of coronary heart disease (CHD) during treatment with CEE/MPA but not CEE alone suggests a direct effect of MPA on the vessel wall. MPA has been demonstrated to upregulate the thrombin receptor, the thrombin-induced production of tissue factor and procoagulatory activity in the vessel wall owing to its glucocorticoid activity. In contrast, CEE alone reduced non-significantly the risk of CHD in women aged 50–59 years, suggesting that primary prevention is possible if estrogen replacement therapy is initiated early. As clinical studies on the effect of different progestogens combined with estrogens are scarce, a possible superiority of progestogens other than MPA remains to be proven.

Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations

Deep vein thrombosis and its lethal complication pulmonary embolism are manifestations of venous thromboembolism (VTE), which is typically associated with cancer and recent major surgery. Certain solid tumors and hematologic malignancies impose an inherently elevated risk of VTE that is compounded by chemotherapy and other risk factors. Multiple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their multiple hemostatic effects, including elevated interleukin-6 levels, pro-coagulant antibody formation, paraprotein interference with fibrin structure, activated protein C resistance, and endothelial damage. The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported. Various VTE prophylaxis strategies with thalidomide- and lenalidomide-containing combinations have been investigated in clinical studies. This review discusses emerging results on the use of VTE prophylaxis to minimize VTE risks associated with MM treatment regimens containing thalidomide and lenalidomide.

Cardiovascular Events Associated With Different Combined Oral Contraceptives

Studies of combined oral contraceptive (COC) use and cardiovascular disease have been conducted against a background of low cardiovascular risk in young women, changing COC composition and changing user selection and monitoring. Studies of myocardial infarction have found inconsistent results, possibly because of differences in the prevalence of risk factors (particularly smoking and raised blood pressure) in the populations studied. In the absence of a history of smoking and other conventional risk factors, current users of modern COCs probably do not have an increased risk of myocardial infarction. Neither are former users at risk. Evidence for important differences in the risk of myocardial infarction between formulations is weak and contradictory. Current users of low estrogen dose COCs have a small increased risk of ischaemic stroke although most of the risk occurs in women with other risk factors (notably smoking, hypertension and probably a history of migraine). Former users of COCs do not have an increased risk of ischaemic stroke. There is insufficient information to determine whether major differences in the risk of ischaemic stroke exist between products. Current users appear to have a modestly elevated risk of haemorrhagic stroke, mainly in women older than 35 years; former users do not. Data examining the risk of haemorrhagic stroke in current COC users with other risk factors are very sparse, as are those relating to the haemorrhagic stroke risk associated with particular COCs. Numerous studies have found, with remarkable consistency, an elevated risk of venous thromboembolism among current users of low estrogen dose COCs. The risk is substantially elevated among women with various inherited clotting factor defects. The effects in COC users with other risk factors for venous thrombosis tend to be less pronounced and more inconsistent. A number of studies have found higher relative risks among current users of low estrogen dose COCs containing desogestrel or gestodene, than among users of similar products containing levonorgestrel. A number of explanations, in terms of bias or confounding, have been proposed for these clinically small differences. At best, empirical evidence for these explanations, is weak. The risk of cardiovascular disease of any description is low in COC users. Women can minimise, and possibly eliminate entirely, their arterial risks by not smoking and by having their blood pressure checked before using a COC (in order to avoid its use if raised blood pressure is discovered). Users may decrease their venous thromboembolic risk by their choice of COC preparation although the effects will be modest.

Therapeutic controversy: The safety of third-generation oral contraceptives.

This paper presents the contributions of Drs. Barbieri, Speroff, Walker, and McPherson to the debate on the safety of third-generation oral contraceptives (OCs). In the overview by Barbieri, the issues of how to assess the quality of the evidence and developing a meaningful framework for integrating an analysis of the benefits and risks of a contraceptive hormone are discussed. He also reflects on the leadership role the endocrinologist must assume in better defining the pharmaco-endocrinology of gestodene and desogestrel. Speroff concludes that modern low-dose OCs are very safe. It was noted that the use of OCs yields an overall improvement in individual health, and from a public health point of view the collection of effects associated with OCs leads to a decrease in the cost of health care. In contrast, Walker argues that low-estrogen OCs containing desogestrel and gestodene carry a modestly elevated risk of venous thromboembolism in comparison to other low-estrogen OCs in widespread use. This statement is supported by McPherson, who emphasizes that the risk associated with OCs is real and should be avoided.