Lower Risk Of Recurrent Venous Thromboembolism Research Articles

The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study

The optimal duration of anticoagulation for women who had venous thromboembolism (VTE) associated with estrogen use is unknown. To test the hypothesis that women who had a first VTE while using estrogens have a low risk of recurrence. A Prospective cohort study of 630 women (333 estrogen users, 297 non-users) with a first VTE, who were followed for an average of 69 months after anticoagulation withdrawal. Women with a previous or secondary VTE, coagulation inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, requirement of long-term antithrombotic therapy or homozygosity or double heterozygosity for factor V Leiden and/or the G20210A prothrombin mutation were excluded. The endpoint was objectively documented symptomatic recurrent VTE. VTE recurred in 22 (7%) estrogen users and in 49 (17%) non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% confidence interval [CI], 0-2), 1% (95% CI, 0-2) and 6% (95% CI, 3-9) among estrogen users and 5% (95% CI, 2-7), 9% (95% CI, 6-13) and 17% (95% CI, 12-22) among non-users. Compared with non-users, estrogen users had an adjusted relative risk (RR) of recurrent VTE of 0.4 (95% CI, 0.2-0.8). Compared with non-users in the respective age groups, the RR of recurrence was 0.4 (95% CI, 0.2-0.8) among estrogen-containing-contraceptive users and 0.7 (95% CI, 0.3-1.5) among women using estrogen-containing menopausal hormone therapy. Women who had their first VTE while using estrogens have a low risk of recurrent VTE. These women might not benefit from extended anticoagulant therapy.

The Risk Of Recurrence In Women With Venous Thromboembolism While Using Estrogens: A Prospective Observational Cohort Study

▪ ObjectiveBecause of the high recurrence risk, guidelines recommend indefinite anticoagulation in women with a first unprovoked proximal deep-vein thrombosis (DVT) and/or pulmonary embolism (PE). The optimal duration of anticoagulation in women who had venous thromboembolism (VTE) while using estrogens is unknown. We therefore compared the risk of recurrent VTE between women who used estrogens at the time of first VTE and women who did not. MethodsThis analysis was performed within the frame of the Austrian Study on Recurrent Venous Thromboembolism (AUREC), an on-going prospective observational study. Patients with a first objectively confirmed DVT of the leg and/or PE who had received anticoagulants for 3 to 18 months were included. Exclusion criteria were: age < 18 years; VTE associated with surgery, trauma, cancer or pregnancy; long-term anticoagulation; natural inhibitor deficiency; lupus anticoagulant; homozygosity or double heterozygosity for factor V Leiden and/or the prothrombin mutation. Women were advised to refrain from further estrogen use and were excluded in case of non-adherence. The study end point was recurrent symptomatic DVT and/or PE verified by imaging. The local ethics committee approved the study and all patients gave written informed consent. ResultsWe followed 630 women (mean age 46 +/- 17 years) who had been treated with oral anticoagulants for 7 (+/- 3) months for an average of 69 (+/- 52) months. Recurrent VTE was recorded in 71 patients (11%). Recurrent VTE occurred in 22 (7%) of 333 estrogen users and in 49 (17%) of 297 non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% CI 0-2), 1% (95% CI 0-2) and 6% (95% CI 3-9) among estrogen users and 5% (95% CI 2-7), 9% (95% CI 6-13) and 17% (95% CI 12-22) among non-users, respectively (p < 0.001, Figure). Compared to non-users, estrogen users had a relative risk (RR) of recurrent VTE of 0.4 (95% CI 0.2-0.8) after adjustment for age, site of first VTE and factor V Leiden carrier status. Compared to non-users in the respective age groups, the RR of recurrent VTE was 0.4 (95% CI 0.2-0.8) among estrogen containing contraceptive users and was 0.7 (95% CI 0.3-1.5) among women using estrogen containing hormone replacement therapy. [Display omitted] ConclusionWomen who had their first VTE while using estrogens have a low risk of recurrent VTE. The recurrence risk is particularly low in estrogen containing contraceptive users. We therefore propose that these women should receive anticoagulant therapy for no longer than 3 months. Disclosures:No relevant conflicts of interest to declare.

Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study

ObjectivesStatins may decrease the risk of primary venous thromboembolism (VTE), that is, deep vein thrombosis (DVT) and pulmonary embolism (PE) but the effect of statins in preventing recurrent VTE is...

Relationship Between Subtherapeutic Warfarin Anticoagulation and the Development of Post Thrombotic Syndrome After a First Unprovoked Deep Vein Thrombosis: Results From the REVERSE Cohort Study

Abstract 712 Background & Objective:Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS. Methods:The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence.For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of > 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR <2 for more than 20% of the time was considered to represent subtherapeutic anticoagulation. Univariate analysis was performed to determine the odds ratio (OR) for development of PTS if anticoagulation was considered subtherapeutic. Multivariate analysis was then performed to adjust for known confounding variables. Results:646 patients were enrolled into the REVERSE study, of whom 410 had DVT as their index event. Of these, 61 were excluded for insufficient INR or PTS data. Hence, the study population comprised 349 patients. The average age was 54.2 years, and 55.6% of the patients were male. Patients were on oral anticoagulation for a mean (SD) of 199 (17) days. Ninety-seven patients (27.8%) developed PTS; of these, 77 (74.7%) had mild PTS, 16 (15.5%) had moderate PTS and 4 (3.9%) had severe PTS.For the study population, the overall mean (SD) TTR during oral anticoagulation was 64.3% (19.4%) and the overall mean (SD) percentage time spent with an INR under 2 was 23.7% (18.7%). For the time window ‘first 3 months of anticoagulation’, patients who developed PTS had an INR of <2 for 30% of the time vs. 24% of the time in patients without PTS (p=0.023). For the time window ‘full period of anticoagulation’, patients who developed PTS had INR <2 for 27% of the time vs. 23% of the time in patients without PTS (p=0.08). Using our predefined cut-off for subtherapeutic anticoagulation (i.e. INR <2 for more than 20% of the time), patients with PTS were more likely to have received subtherapeutic anticoagulation than those without PTS during the first 3 months of anticoagulation (62.9% vs. 48.8%; p=0.02) and during the full period of anticoagulation (62.9% vs. 48.0%; p=0.01). The incidence of PTS in patients with an INR below 2 for >20% of the full time period was 33.5% compared to 21.6% in those with an INR below 2 for ≥20% of the time (p=0.02).In univariate analysis, the OR for development of PTS if the INR was <2 for more than 20% of the time during the first 3 months of anticoagulation was 1.78 (95% CI 1.10–2.87). In multivariate analysis adjusting for age, sex, body mass index, concurrent PE, previous secondary VTE and use of graduated compression stockings, the association between subtherapeutic anticoagulation and PTS remained robust (1.84 95% CI 1.13–3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14–3.00) [crude] and 1.88 (95% CI 1.15–3.07) [adjusted]. Conclusion:Subtherapeutic warfarin anticoagulation after a first unprovoked DVT may be a risk factor for the development of PTS. Careful attention to INR control may have value in preventing PTS. Further study of the risk of PTS associated with oral or parenteral anticoagulants that offer more predictable anticoagulation than warfarin may be of value. Disclosures:No relevant conflicts of interest to declare.

Identification of Patients At High Risk for Recurrent Venous Thromboembolism by Whole Blood Gene Expression Analysis

Abstract 2305 Background.Recurrent venous thromboembolism (VTE) occurs in ∼30% of patients with spontaneous VTE after completion of a standard course of anticoagulant therapy. D-dimer levels and selected clinical parameters have been used to identify patients at low risk for recurrent VTE, who may safely discontinue antithrombotic therapy. We have used gene expression profiles to distinguish patients with a single VTE from patients with recurrent VTE. The purpose of this study was to extend this initial report and identify unique gene expression patterns from whole blood that correlate with different risk profiles for VTE recurrence. Methods.Patients with ≥1 prior VTE, with the first event occurring at age 18 years or older and >3 months from the most recent event were recruited for this study. Patients were allocated into 4 groups: (1) ‘low-risk' patients had sustained ≥1 provoked VTE; (2) ‘moderate-risk' patients had sustained 1 unprovoked VTE (with or without provoked VTE); (3) ‘high-risk' patients had sustained ≥2 unprovoked VTE and had no evidence for antiphospholipid antibodies; and (4) antiphospholipid syndrome (APS) patients met established consensus criteria for APS. A similar number of individuals with no prior history of VTE were enrolled as a control population. Citrated plasma, serum and PAXgene RNA tubes were collected, processed and stored at −80°C until shipped to the CDC for analysis. Antiphospholipid testing was performed on all participants to confirm correct group distribution. Total RNA was isolated from whole blood drawn into PAXgene tubes. Following sample labeling and normalization, cRNA samples were hybridized to Illumina HT-12 Beadchips to assay whole genome gene expression with over 47,000 probes against human transcripts. Two hundred and twenty six unique samples passed initial quality control measures. Quality assessment of raw data was done using GenomeStudio. The raw data files were converted to a text file using the IlluminaExpression FileCreator in GenePattern and then log transformed, normalized and median-centered using Cluster. Both unsupervised (hierarchical clustering using Cluster) and supervised analyses (SAM) were used to identify genes that were differentially expressed between the groups. GATHER was used to help understand the biological processes and gene ontology of the gene lists generated by Cluster and SAM. Results.A total of 226 participants were enrolled into the study. Characteristics of the patient groups are summarized in the Table. Demographically, the groups were similar except that patients in the high-risk group tended to be older and were more likely male. The number of events per patient, and the proportion on anticoagulant therapy, increased with the risk group.GroupAge, yrSex, F (%)Race, W (%)Time since last VTE, yrPE, N (%)VTE/Patient N (n; %)AC therapy?Low-risk (n=44)49 (25–90)25 (57%)37 (84%)4 (1–15)15 (34%)1 (37; 84%); 2 (7; 16%)31 (70%)Moderate-risk (n=45)53 (22–86)23 (51%)37 (82%)3 (1–9)34 (76%)1 (28; 62%); 2 (15; 33%); 3 (2; 4%)41 (91%)High-risk (n=46)58 (28–82)15 (33%)37 (80%)6 (1–22)25 (54%)2 (29; 63%); 3 (9; 20%) ≥4 (7; 15%)46 (100%)APS (n=47)48 (20–83)24 (51%)43 (91%)7 (1–26)25 (53%)1 (22; 47%); 2 (19; 40%); ≥3 (3; 6%)44 (94%)Normals (n=44)48 (21–75)26 (59%)39 (89%)–0–2 (5%)Antiphospholipid antibodies were detected in several patients in each of the 3 non-APS VTE patient groups, but in most cases this was a single test positive; antiphospholipid antibodies were present in the majority of patients with APS, typically with more than one test positive (37 of 45 with complete testing, 82%). Preliminary analysis of the gene expression profiles using an unsupervised clustering by gene on the high-risk and low-risk groups identified multiple genes that distinguished the two groups, including 18 immune response genes identified by GATHER. These two patient groups were also distinguished by SAM analysis, and multiple genes in the MAPK signaling pathway that separated the two groups were identified by the KEGG pathways in GATHER. Additional analyses are being performed on all of the groups. Conclusions.Whole blood gene expression profiling can be used to develop profiles that distinguish patients with VTE who differ based on their risk of recurrent events. Individual genes identified in these profiles may provide biological insights into the molecular basis for recurrent VTE. Disclosures:Heit:Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria. Manco-Johnson:Octapharma AG: Consultancy; Bayer: Research Funding.

Enoxaparin once daily vs. twice daily dosing for the treatment of venous thromboembolism in cancer patients: A literature summary

Current anticoagulation guidelines for cancer patients are largely based upon studies done in the general population. Anticoagulation studies in cancer patients with venous thromboembolism (VTE) have compared varying doses of different low molecular weight heparins (LMWH) to warfarin or unfractionated heparin (UFH) regimens, and most guidelines recommend LMWH as the preferred agent over vitamin K antagonists. However, very few studies compare different dosing regimens of the LMWH itself. As a result, practitioners attempt to extrapolate results from studies done in the general medicine population and apply them to cancer patients with VTE. Considering the differences in risk factors and hypercoagulability between these populations, such generalizations may compromise outcomes or safety for cancer patients. Currently, no study to date has compared the safety and efficacy of enoxaparin 1.5 mg/kg subcutaneously (SC) once daily vs. 1 mg/kg SC twice daily in a prospective, randomized fashion, for the longterm treatment of VTE in patients with cancer. The purpose of this article is to review currently available literature utilizing these dosing schemes in order to risk-stratify cancer patients who may better qualify for one dosing regimen as compared to the other. Our analysis suggests that enoxaparin dosed at 1.5 mg/kg SC once daily may be a safe and effective alternative for the treatment of VTE in cancer patients with both a low risk of recurrent VTE and bleeding. In the absence of additional studies, the dosing of enoxaparin for cancer patients should be based on patient-specific risk factors.

Gender and the Risk of Venous Thromboembolism

The role of gender in the causation of first and recurrent venous thromboembolism (VTE) is uncertain. The use of hormonal therapy and pregnancy has been associated with VTE in women. Epidemiological studies have described a higher incidence of first VTE in women of childbearing age. Nevertheless, no consistent differences in the overall incidence of VTE between males and females have been found. Recent studies have shown that women exhibit a lower risk of recurrent VTE than men, although these data were not confirmed in other studies that evaluated only women with idiopathic VTE. This article reviews the role of gender as a risk factor for first and recurrent VTE.

Recurrent venous thromboembolism after surgery-provoked versus unprovoked thromboembolism.

The incidence of recurrent venous thromboembolism (VTE) varies depending on the nature of the initial provoking risk factor(s). To compare the incidence and time course of recurrent VTE after unprovoked VTE vs. VTE provoked by nine different types of surgery. Retrospective analysis of linked California hospital and emergency department discharge records. Between 1997 and 2007, all surgery-provoked VTE cases had a first-time VTE event diagnosed within 60 days after undergoing a major operation. The incidence of recurrent VTE was compared during specified follow-up periods by matching each surgery-provoked case with three unprovoked cases based on age, race, gender, VTE event, calendar year and co-morbidity. The 4-year Kaplan-Meier cumulative incidence of recurrent VTE was 14.7% (95%CI: 14.2-15.1) in the matched unprovoked VTE group vs. 7.6% (CI: 7.0-8.2) in 11 797 patients with surgery-provoked VTE (P < 0.001). The overall risk reduction was 48%, which ranged from 64% lower risk (P < 0.001) after coronary bypass surgery to 25% lower risk (P = 0.06) after disc surgery. The risk of recurrent VTE 1-5 years after the index event was significantly lower in the surgery group (HR = 0.47, CI: 0.41-0.53). Within the surgery-provoked group, the risk of recurrent VTE was similar in men and women (HR = 1.0, CI: 0.8-1.3). The risk of recurrent VTE after surgery-provoked VTE was approximately 50% lower than after unprovoked VTE, confirming the view that provoked VTE is associated with a lower risk of recurrent VTE. However, there was appreciable heterogeneity in the relative risk of recurrent VTE associated with different operations.

Risk of recurrent venous thromboembolism after a first oestrogen-associated episode

The use of exogenous oestrogen in women with otherwise unprovoked venous thromboembolism (VTE) could be considered sufficient explanation to classify VTE as provoked if the risk of recurrent VTE after 3-6 months of anticoagulant treatment is similar to the risk of recurrent VTE observed after a surgery or prolonged immobilisation. Our objective was to assess the risk of recurrent VTE in women after a first unprovoked episode on oestrogen. The REVERSE study is a cohort study of patients with a first unprovoked VTE treated with anticoagulant treatment for 5-7 months. The risk of recurrent VTE during follow-up was compared between women users and non users of oestrogen at the time of index VTE. Among the 646 patients included, 314 were women, of them 67 were current users of oestrogen at the time of their VTE: 49 were on oral contraceptives and 18 on post-menopausal hormone replacement therapy (HRT). No significant association was found between oestrogen exposure, either oral contraceptives or HRT, and a lower risk of recurrent VTE after adjustment for age, or analysis restricted to women in the same age range as oestrogen contraceptives and HRT users, respectively. The risk of recurrent VTE is low in women after a first otherwise unprovoked oestrogen-associated VTE. However, this risk is not significantly lower than in women whose VTE was not related to oestrogen use.

A Clinical Perspective of Venous Thromboembolism

A large number of individuals develop venous thromboembolism (VTE) every year.1 Each patient’s episode of DVT or PE is, naturally, unique. To highlight a variety of aspects about VTE a compilation case is presented that is composed of clinical data and images from several real patients. ### History of Present Illness A 36-year-old woman presents to the Emergency Department with severe shortness of breath and moderately intense anterior chest pain, worse on deep inspiration, which had started suddenly that morning. She also reports a 6-wk history of mild shortness of breath, for which she had been seen 4 wk earlier by her primary care physician who diagnosed her with “asthma.” Bronchodilators and steroids were prescribed but led to no significant improvement in her symptoms. She also gives a history of mild left calf pain that had started about 2 months earlier without preceding trauma, immobilization, or surgery. Her primary care physician had seen her and prescribed Ibuprofen for a “pulled muscle.” However, in the 1 week before her present presentation her leg symptoms worsened, and she had increased diffuse leg pain and swelling and slightly bluish discoloration of the whole leg. Her past medical history is only significant for an appendectomy at age 16. She has never been pregnant. She is on no medications, except for an estrogen and progestin-containing oral contraceptive, started 10 months earlier. She does not smoke. There is no family history of venous thromboembolism, although the patient reports that her paternal grandmother had a “swollen leg for many years” until she died in her 70’s, but no further details are known of the patient. ### Physical Examination The patient’s weight is 86 kg and her height 165 cm, calculating to a body mass index (weight divided by [height in meters]2) of 31.6 kg/m2, ie, she has grade 1 obesity. Her …

Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism

It is not known whether women who develop venous thromboembolism (VTE) during pregnancy have a higher or lower incidence of recurrent VTE than women with unprovoked VTE. The aim of the study was to compare the risk of recurrent VTE among women with pregnancy-associated VTE to women with unprovoked VTE. Hospital discharge data identified women age 18-46 years old with pregnancy-associated or unprovoked index VTE between 1994 and 2005. Risk of recurrent VTE was compared between six and 60 months after the index event using both age-matched comparison of disease-free survival and proportional hazard modelling, adjusting for age and other risk factors. The Kaplan-Meier incidence of recurrent VTE in 1085 women with pregnancy-associated VTE was 5.8% versus 10.4% in 7625 women with unprovoked VTE (p = 0.02). Twelve of 34 (35%) recurrent events in the pregnancy-associated group occurred during a subsequent pregnancy compared with 29 of 331 (8.7%) events in the unprovoked group (p < 0.001). In the risk-adjusted multivariate model, women with pregnancy-associated VTE had a significantly lower risk of recurrent VTE (HR = 0.6, 95%CI = 0.4-0.9). Overall, the incidence of recurrent VTE during subsequent pregnancies was higher in the pregnancy group, 21 of 465 (4.5%), than in the unprovoked group, 37 of 1353 (2.7%, RR = 1.7, CI: 1.0-2.8). Compared to women with unprovoked VTE, women with pregnancy-associated VTE had a significantly lower long-term risk of recurrent VTE but a higher risk of recurrent VTE during a subsequent pregnancy. These findings should be considered when decisions are made about VTE prophylaxis in women with a history of pregnancy-associated VTE.

Prediction of recurrent venous thromboembolism by measuring ProC Global

In patients with venous thromboembolism (VTE) a laboratory assay that globally measures the overall thrombophilic tendency is not available. We hypothesized that determination of ProC((R)) Global, a plasma assay which tests the global function of the protein C pathway, could be used to stratify patients according to their risk of recurrent VTE. We prospectively followed 774 patients with first spontaneousVTE for a mean time of 52 months. ProC Global normalized ratio (NR) was measured in plasma by use of a commercially available assay based on activated partial thromboplastin time. Ninety-eight of the 774 patients had recurrentVTE. Patients with ProC Global NR > or = 0.75 had a relative risk of recurrence of 0.59 (95% CI 0.40-0.87) as compared with those with lower ratio. After four years, cumulative probability of recurrence was 8.6% in patients with ProC Global NR > or = 0.75 and 17.4% in patients with a lower ratio (p = 0.006). Patients with a high ProC Global NR have a low risk of recurrent VTE. ProC Global NR can be used to stratify patients with a first unprovoked VTE according to their risk of recurrence.

Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation

Screening of patients with venous thromboembolism (VTE) for thrombophilic risk factors is common clinical practice. Because of the large number of risk factors, assessing the risk of recurrence in an individual patient is complex. A method covering multicausal thrombophilia is therefore required. To investigate the relationship between recurrence of VTE and a simple global coagulation assay measuring thrombin generation. Prospective cohort study of 914 patients with first spontaneous VTE who were followed up for an average of 47 months after discontinuation of vitamin K antagonist therapy. The study was conducted at the Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria, between July 1992 and July 2005. Thrombin generation was measured by a commercially available assay system. Patients with a previous or secondary VTE; antithrombin, protein C, or protein S deficiencies; presence of lupus anticoagulant; cancer; or pregnancy were excluded. Objectively documented symptomatic recurrent VTE. Venous thromboembolism recurred in 100 patients (11%). Patients without recurrent VTE had lower thrombin generation than patients with recurrence (mean [SD], 349.2 [108.0] nM vs 419.5 [110.5] nM, respectively; P<.001). Compared with patients who had thrombin generation greater than 400 nM, the relative risk (RR) of recurrence was 0.42 (95% confidence interval [CI], 0.26-0.67; P<.001) in patients with values between 400 nM and 300 nM; for patients with lower values, the RR was 0.37 (95% CI, 0.21-0.66; P = .001). After 4 years, the probability of recurrence was 6.5% (95% CI, 4.0%-8.9%) among patients with thrombin generation less than 400 nM compared with 20.0% (95% CI, 14.9%-25.1%) among patients with higher values (P<.001). Patients with thrombin generation less than 400 nM, representing two thirds of patients, had a 60% lower RR of recurrence than those with greater values (RR, 0.40; 95% CI, 0.27-0.60; P<.001). Measurement of thrombin generation identifies patients at low risk for recurrent VTE.