Long-term Low Molecular Weight Heparin Research Articles

First three months of anticoagulation for venous thromboembolism in non-cancer patients: LMWH VS. VKAs. Findings from the RIETE registry

BackgroundThe use of low-molecular-weight heparin (LMWH) for long-term therapy of venous thromboembolism (VTE) in patients without cancer has not been consistently evaluated. MethodsWe used the data in the RIETE registry to compare the 3-month outcomes (VTE recurrences, major bleeding or death) in non-cancer patients with VTE, according to long-term therapy with LMWH or vitamin K antagonists (VKAs). ResultsAs of March 2018, 14,582 non-cancer patients with VTE had received initial therapy with LMWH and then switched to VKAs, while 9151 were prescribed LMWH for initial and long-term therapy. Overall, 11,494 had initially presented with pulmonary embolism (PE) and 12,239 with isolated deep vein thrombosis (DVT). Among 11,494 patients initially presenting with PE, 84 had VTE recurrences, 204 major bleeding and 406 died. Among 12,239 patients with isolated DVT, 133 developed VTE recurrences, 137 bled and 289 died. On propensity score analysis, PE patients on long-term LMWH therapy were at increased risk for PE recurrences (OR: 3.30; 95%CI: 1.67–6.48), major bleeding (OR: 1.68; 95%CI: 1.21–2.32) or death (OR: 3.16; 95%CI: 2.43–4.09) compared with those receiving VKAs. In patients with DVT, those on long-term LMWH also were at increased risk for PE recurrences (OR: 2.31; 95%CI: 1.13–4.73), major bleeding (OR 2.28; 95%CI: 1.51–3.44) or death (OR: 2.32; 95%CI: 1.54–3.51). ConclusionsIn the RIETE non-cancer patients with VTE, long-term therapy with VKAs was associated with a lower risk for recurrences, major bleeding or death.

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update.

To provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs published from August 1, 2014, through December 4, 2018. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. The systematic review included 35 publications on VTE prophylaxis and treatment and 18 publications on VTE risk assessment. Two RCTs of direct oral anticoagulants (DOACs) for the treatment of VTE in patients with cancer reported that edoxaban and rivaroxaban are effective but are linked with a higher risk of bleeding compared with low-molecular-weight heparin (LMWH) in patients with GI and potentially genitourinary cancers. Two additional RCTs reported on DOACs for thromboprophylaxis in ambulatory patients with cancer at increased risk of VTE. Changes to previous recommendations: Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE.Additional information is available at www.asco.org/supportive-care-guidelines.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer.

Quality of life in cancer patients undergoing anticoagulant treatment with LMWH for venous thromboembolism: the QUAVITEC study on behalf of the Groupe Francophone Thrombose et Cancer (GFTC).

BackgroundClinical guidelines recommend at least 3-months low molecular weight heparin (LMWH) treatment for established venous thromboembolism (VTE) in cancer patients. However, no study has analyzed the impact of 3–6 months of LMWH therapy on quality-of-life (QoL) in cancer patients.ResultsAmong 400 cancer patients included at M0, 88.8% received long-term LMWH. Using a random-effects linear regression model with time as covariate, QoL scores in the MOS SF-36 (Global HRQoL, 1.3-fold per month [95% confidence interval (CI) 0.81–1.79], p < 0.0001) and EORTC QLQ-C30 (global health status/qol, 2.25-fold per month [95% CI 1.63–2.88]; p < 0.0001) questionnaires significantly improved over the 6-month study period in patients treated with LMWH, while VEINES-QOL scores did not change. In the MOS SF-36 and EORTC QLQ-C30, the following factors were associated with change in QoL: symptomatic VTE, cancer dissemination and histological type. Factors pertaining to reduced mobility were also identified as significant predictors of QoL outcomes, including being bedridden in the MOS SF-36 and ECOG score ≥ 2 in the EORTC QLQ-C30. Presence of acute infection and not undergoing anti-angiogenic therapy were additional factors associated with QoL improvement in the EORTC QLQ-C30.MethodsQUAVITEC, a prospective, longitudinal, multicenter study, recruited all consecutive eligible adult cancer patients with objectively confirmed VTE between February 2011 and 2012. Patients were asked to answer three QoL questionnaires at anticoagulant treatment initiation (M0) and at 3 (M3) and 6 (M6)-month follow-ups.ConclusionQUAVITEC is the first study to show that QoL was improved in cancer patients receiving long-term LMWH treatment for established VTE.

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Safety of Weight-Adjusted Dosing of LMWH in Clinically Obese Cancer Patients with Venous Thromboembolism

Background: Obesity, defined as a body mass index (BMI) greater than 30 kg/m2, is a well-known risk factor for venous thromboembolism (VTE). Despite this observation, obese patients are under-represented in anticoagulation safety trials. Current guidelines recommend patients with active malignancy and VTE to be treated with long-term low molecular weight heparin (LMWH), but it is unclear whether this practice is safe in obese cancer patients.Objectives: We hypothesized there would be an increased risk of major or clinically significant non-major bleeding in obese cancer patients receiving long-term, actual weight-adjusted LMWH compared to non-obese patients with cancer- associated VTE.Methods: We conducted a single centre retrospective cohort study of obese cancer patients referred to our thrombosis clinic from January 2010 to December 2015. We included all obese cancer patients assessed at the Thrombosis unit who received anticoagulation with LMWH. Obesity was defined as weight above 90 Kg or BMI of 30 kg/m2 or more. The obese patients’ data was compared to a non-obese control group of patients with active malignancy treated with LMWH. Major bleeding was defined as a hemoglobin drop of > 20 g/L; clinically overt bleeding; bleeding requiring 2 units or more of packed red blood cells; a hemorrhage requiring permanent cessation of anti-coagulation; or any retroperitoneal or intracranial hemorrhage. Diagnosis of deep venous thrombosis was confirmed when compression ultrasound of the lower extremities showed evidence of thrombus in the calf trifurcation or more proximal veins; or calf thrombosis associated with pulmonary embolism (PE). PE was confirmed when the ventilation-perfusion lung showed at least a large mismatched defect or CT pulmonary angiography demonstrated at least one segmental intra-luminal filling defect.Results: In total, 102 obese cancer patients and 81 non-obese cancer patients met our eligibility criteria. In the obese cohort, 43 (42%) were male, median age 64 (24-89), median weight 96.5 kg (67.3-158), and median BMI 33.7 kg/m2 (27.2-57). 90 (88%) patients had a solid tumour. Median dose of LMWH was 18,000 units (10,000 - 30,000): 78 (76%) were prescribed dalteparin and 22 (22%) tinzaparin. Median follow-up was 191 days (3 - 2622). Baseline characteristics of the control group were similar (Table 1). Total bleeding episodes were significantly different in the 2 groups: total bleeding events were 10 (9.8%) in the obese group (4 were under-dosed based on their weight) and 1 in the control group [RR=7.9; 95% CI (1.04 -60.76) p=0.046)]. Major bleeding events occurred in 6 (5.9%) obese and in none of the non-obese patients [RR=10.4; 95% CI (0.59 -181.05) p=0.11)]. Platelet counts were appropriate in all cases but one, where a non-major bleed occurred in an obese patient with a platelet count of 27. Recurrent VTE occurred in 8 (7.8%) obese and 4 control patients. In the obese cohort, 5 of those patients were receiving under-dosed LMWH based on their weight. There was no statistically significant difference regarding VTE recurrence risk in the obese and control groups [RR=1.59; 95% CI (0.50 -5.09) p=0.44)]. Interestingly, 31 of 96 obese patients (31%) with BMI 30 or above weighed less than 90 kg.Conclusions: Our findings differ from the available literature. In the CLOT trial, total and major bleeding episodes in the LMWH group occurred in 14% and 7%, respectively, with VTE recurrence of 9%. In comparison, our results demonstrate total and major bleeding episodes in our obese cancer patients on LMWH of 9.8% and 5.9%, respectively, with VTE recurrence of 7.8%. Total bleeding was statistically significant compared to a non-obese cancer population, however, limitations in sample size and event rate need to be taken into consideration when interpreting these results. [Display omitted] DisclosuresKovacs:Daiichi Sankyo Pharma: Research Funding; Bayer: Honoraria, Research Funding; LEO Pharma: Honoraria; Pfizer: Honoraria, Research Funding. Lazo-Langner:Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. Louzada:Celgene: Consultancy, Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Janssen: Consultancy, Honoraria.

Venous thromboembolism in centenarians: Findings from the RIETE registry

BackgroundThe balance between the efficacy and safety of anticoagulant therapy in patients aged ≥100years receiving anticoagulant therapy for venous thromboembolism (VTE) is uncertain. MethodsWe used data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to assess the rate of VTE recurrences, bleeding events, and mortality appearing during the course of anticoagulant therapy in VTE patients aged ≥100years. ResultsOf 61,173 patients enrolled in RIETE as of January 2016, 47 (0.08%) were aged ≥100years. Of these, 10 (21%) were men, 21 (45%) presented with pulmonary embolism (PE), and 26 with deep vein thrombosis alone. Overall, 35 patients (74%) had severe renal insufficiency, 14 (30%) chronic heart failure, 30 (64%) anemia, 16 (34%) were taking antiplatelets, and 6 (13%) corticosteroids or non-steroidal anti-inflammatory drugs. Most patients (95%) were treated initially with low-molecular-weight heparin (LMWH) (mean daily dose, 168±42IU/kg). Then, 14 (30%) switched to vitamin K antagonists and 29 (62%) kept receiving long-term LMWH therapy (mean, 148±51IU/kg/day). During the course of anticoagulant therapy (mean duration, 139days), mortality was high (15/47; 32%). Two patients died of PE (initial PE one, recurrent PE one) and 5 (11%) had minor bleeding, but no major bleeding was reported. ConclusionsAmong patients with acute VTE aged ≥100years, the risk of VTE recurrences during the course of anticoagulation outweighed the risk of bleeding. Our data suggest the use of standard anticoagulant therapy in this patient population, even if they have severe renal insufficiency.

Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis.

Adults who require long-term anticoagulation with low-molecular-weight heparin (LMWH) such as cancer patients or the elderly may be at increased risk of fractures. To determine the effects of LMWH therapy of at least 3months' duration on fractures and bone mineral density (BMD) in non-pregnant adult populations. We systematically reviewed electronic databases (e.g., MEDLINE, EMBASE), conferences and bibliographies until June 2015 and included comparative studies in non-pregnant adult populations that examined the effects of LMWH (≥3months) on fractures and BMD. We synthesized evidence qualitatively and used random-effects meta-analysis to quantify the effect of LMWH on fractures. Sixteen articles reporting 14 studies were included: 10 clinical trials (n = 4865 participants) and four observational cohort studies (3 prospective, n = 221; 1 retrospective, n = 30). BMD and fractures were secondary outcomes in the majority of trials, while they were primary outcomes in the majority of observational studies. In participants with venous thromboembolism and underlying cardiovascular disease or cancer (5 RCTs, n = 2280), LMWH for 3-6 months did not increase the relative risk of all fractures at 6-12 months compared to unfractionated heparin, oral vitamin K antagonists or placebo [pooled risk ratio (RR) = 0.58, 95 % CI: 0.23-1.43; I(2) = 12.5%]. No statistically significant increase in the risk of fractures at 6-12 months was found for cancer patients (RR = 1.08, 95 % CI: 0.31-3.75; I(2) = 4.4%). Based on the data from two prospective cohort studies (n = 166), LMWH for 3-24 months decreased mean BMD by 2.8-4.8% (depending on the BMD site) compared to mean BMD decreases of 1.2-2.5% with oral vitamin K antagonists. LMWH for 3-6 months may not increase the risk of fractures, but longer exposure for up to 24months may adversely affect BMD. Clinicians should consider monitoring BMD in adults on long-term LMWH who are at increased risk of bone loss or fracture.

Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26–3.23), age >70 years (OR 1.15, 95% CI 1.06–1.24), immobility (OR 2.06, 95% CI 1.93–2.19), renal insufficiency (OR 2.42, 95% CI 2.15–2.71) and anemia (OR 1.75, 95% CI 1.65–1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64–2.06), immobility (OR 1.51, 95% CI 1.30–1.76) and metastases (OR 3.22, 95% CI 2.87–3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.

Long-Term Efficacy and Safety of Low-Molecular-Weight Heparins (LMWH) for Cancer-Associated Venous Thromboembolism (VTE) in Tropique, a Prospective Non-Interventional Observational Study

▪IntroductionLong-term treatment with LMWH is the standard therapy for patients with cancer-associated VTE. Recommended treatment regimen include the prescription of LMWH at treatment doses according to approved administration schedule for at least 3 months in the absence of severe renal insufficiency (CrCl<30 mL/min) [1, 2]. The TROPIQUE study documented the prescription and use of long-term treatment with LMWH in cancer patients. Here we report the findings on the secondary outcomes, clinical efficacy and safety.MethodsAdult patients with cancer-associated VTE receiving antineoplastic treatment or palliative care were eligible to participate. Efficacy outcomes measures were VTE recurrence including deep-vein thrombosis (DVT) and pulmonary embolism (PE), visceral thrombosis and central venous catheter (CVC)-associated thrombosis. Safety outcomes included all and major bleeding according to ISTH definition [3], thrombocytopenia and deaths. Incidences of 7% of VTE recurrence and 6% of major bleeding were expected. With a sample of 384 patients, the rate of VTE recurrence and major bleeding would be detected with a precision of ±2.6% and ±2.4%, respectively, with a 95% confidence interval. A total of 400 patients were therefore planned to be included in the study.ResultsA total of 409 patients with symptomatic cancer-associated VTE (Table 1) aged 65±12.1 years of whom 49.9% female were consecutively included from November 2012 to August 2013. A history of previous VTE was found in 54 (13.2%), surgery or trauma in 100 (24.4%), CVC in 303 (74.1%) and an immobilization over 1 month in 47 (11.5%) patients, respectively. At study inclusion, 30 (7.3%) patients had platelet count ≤ 100 x109/L, and 129 (31.5%) had reported anemia while 16 (3.9%) patients had a history of bleeding in the last month. At baseline, more than 80% of patients presented with at least a PE or a lower-limb DVT of s.Table 1VTE diagnosis at baseline (patients at least with one of the following)VTE diagnosis (at least one of the following)n (%)PE145 (35.5)DVT lower limb193 (47.2)Proximal107 (56.0)Distal72 (37.7)DVT upper limb45 (11.0)Visceral thrombosis16 (3.9)CVC-associated thrombosis66 (16.1)Mean treatment duration was 5.28 ± 2.07 months. As the majority of patients were treated with tinzaparin (73.6%), clinical outcomes are therefore presented for tinzaparin, other LMWH and all LMWH (Table 2).A total of 21 events of VTE recurrence occurred in 19 patients during the overall study period, with a Kaplan-Meir estimate of the probability of VTE recurrence at 6 months of 6.1%.Table 2Outcomes in patients with cancer-associated VTE treated with long-term LMWH [n (%)].Patients treatedTinzaparin n=301Other LMWH n=108All LMWH n=409Patients documentedn=292n=100n=392Patients with at least14 (4.8)5 (5)19 (4.8)one VTE recurrence---Events (2 patients had347more than one event)516DVT011PE617Visceral thrombosisCVC-associated thrombosisBleedingn=292n=100n=392All44 (15.1)11 (11.0)55 (14.0)Major16 (5.5)7 (7.0)23 (5.9)Thrombocytopenian=290n=100n=390(n platelets/mm3)53 (18.3)15 (15.0)68 (17.4)Alln=65n=17n=82< 50,00022527Drop > 50%15217Deathsn=301n=107n=408All102 (33.9)44 (41.1)146 (35.8)Cause of death*n=100n=44n=144LMWH treatment**1#01##Cancer8739126Sepsis415Bleeding415Antineoplastic treatment101PE011Other7310*Multiple causes of death may have been reported in the same patient; **fatal bleeding reported as LMWH-related; #n=99;## n=143Kaplan-Meier estimate of the probability of bleeding at 6 months was 15.9% while corresponding estimates were 18.1% for thrombocytopenia and 34.5% for deaths. Of the five (3.5%) patients who reported fatal bleedings one was reported as related to the LMWH treatment. No heparin-induced thrombocytopenia was reported in the study.ConclusionClinical outcomes were consistent with previous observations in this patient population except a lower incidence of VTE recurrence compared with previous studies. Study results tend to confirm the favorable efficacy and safety profile of LMWH for the long-term treatment of patients with cancer-associated VTE, when used according to recommended treatment duration and respecting contra-indications. 1.Schulman. J Throm Haemost. 2005 Apr;3(4):692-4.2.Farge J Thromb Haemost. 2013 Jan;11(1):56-70.3.Debourdeau P, J Thromb Haemost. 2013 Jan;11(1):71-80 DisclosuresFarge:Pfizer: Research Funding; LEO Pharma: Research Funding. Debourdeau:Pfizer: Research Funding; LEO Pharma: Research Funding. Cajfinger:Pfizer: Research Funding; LEO Pharma: Research Funding.

Long-Term Use of Low-Molecular-Weight Heparin (LMWH) for Cancer-Associated Venous Thromboembolism (VTE): Adherence to Recommendations in Clinical Practice Based on Tropique, a Prospective Non-Interventional Observational Study

IntroductionFew data are available on the long-term LMWH prescription and treatment follow-up in clinical practice in patients with cancer-associated VTE.Study objectives were to document the prescription and use of treatment doses of LMWH in cancer patients and to assess adherence to established recommendations.MethodsAdult cancer patients receiving antineoplastic treatment or palliative care, age ≥18 years, with recent symptomatic VTE in whom treatment with LMWH had been initiated within 7 days prior to inclusion, were eligible to participate in this prospective observational French multicenter study. Patients with a contra-indication to LMWH were not eligible for participation. Main study outcome was the description of LMWH use and prescription in usual medical care. Adherence to recommendations was measured as the proportion of patients receiving a prescription of a LMWH at treatment doses according to the approved dosing schedule and treated for at least 3 months in the absence of severe renal insufficiency (CrCl<30 mL/min) [1, 2]. Assuming a normal patient distribution and the unfavorable hypothesis that only 50% of patients were treated according to the national recommendations, 384 patients were needed to obtain conclusive results with a precision of 5% and a risk error of 5%.ResultsA total of 409 patients aged 65±12.1 years of whom 49.9% female were consecutively included from November 2012 to August 2013. A history of previous VTE was found in 54 (13.2%), surgery or trauma in 100 (24.4%), central venous catheter (CVC) in 303 (74.1%) and immobilization >1 month in 47 (11.5%) patients, respectively. Four (1.03%) patients had severe renal insufficiency.VTE diagnosis at inclusion included lower-limb deep-vein thrombosis (DVT) in 193 (47.2%), pulmonary embolism in 145 (35.5%), CVC-associated thrombosis in 66 (16.1%), upper-limb DVT in 45 (11.0%) and visceral thrombosis in 16 (3.9%) patients, respectively.Most cancers were solid tumors gastro-intestinal (24.4%), lung (17.4%) or breast (15.9%); 81% of patients received chemotherapy and 61.4% were metastatic cancers. LMWH prescriptions included dalteparin in 42 (10.3%), enoxaparin in 61 (14.9%), nadroparin in 5 (1.2%) and tinzaparin in 301 (73.6%) patients. Only 4 (1%) patients received LMWH despite severe renal insufficiency. Table 1 –Prescription adherence to recommendations at inclusion [n (%)]Adherence criteriaTinzaparin (N=301)Other LMWH (N=108)All (N=409)Treatment duration > 3 months293 (97.3)108 (100)401 (98.0)Adequate dosing regimen*231 (76.7)14 (13.0)245 (59.9)Adequate dosing schedule296 (98.3)45 (41.7)341 (83.4)Overall adherence219 (72.8)7 (6.5)226 (55.3)*includes adequate treatment dose and dose adjustment according to recommendationsA total of 274 (67.0%) patients received the recommended treatment dose, while 87 (21.3%) patients received doses exceeding this by more than 10% and 39 (9.5%) patients received doses more than 10% below the recommended doses.Based on the pre-defined adherence criteria, 226 (55.3%) [95% CI 50.4-60.1] patients had a LMWH prescription consistent with recommendations. Tinzaparin prescriptions were associated with higher adherence scores compared to other LMWH.During follow-up, actual mean treatment duration was 5.28 ± 2.07 months and 85.7% of patients were treated for 3 months or moreTable 2 -Adherence to recommendations at inclusion according to cancer characteristics (N=409) [n (%)]Cancer characteristicsProportion of study populationProportion of adherence to recommendationsGastro-intestinal Lung Breast Hemato lymphopoietic Other Metastatic Chemotherapy (n=405)*100 (24.4) 71 (17.4) 65 (15.9) 54 (13.2) 119 (29.1) 251 (61.4) 328 (81.0)53 (53.0) 37 (52.1) 46 (70.8) 28 (51.9) 62 (52.1) 133 (53.0) 186 (56.7)*405 patients documented with chemotherapyAt inclusion, the rate of prescriptions consistent with recommendations was low (55.3%) while the highest rate of adherence (70.8%) was observed in patients with breast cancer known to be at rather lower risk of VTE recurrence.ConclusionAdherence to treatment duration was adequate whereas dosing regimen was insufficiently compliant with recommendations. Overall adherence with tinzaparin seemed higher compared to other LMWH Management of patients with cancer-associated VTE requires further education and information of health care professionals. 1.Farge D, J Thromb Haemost. 2013 Jan; 11(1):56-70. DisclosuresFarge:Pfizer: Research Funding; LEO Pharma: Research Funding. Debourdeau:Pfizer: Research Funding; LEO Pharma: Research Funding. Cajfinger:Pfizer: Research Funding; LEO Pharma: Research Funding.

Long-term treatment with low-molecular-weight heparin prolonged the survival time for acute pulmonary embolism patients concurrent with malignancy: An observational analysis from a long-term follow-up study

BackgroundAs a special group in pulmonary embolism (PE), the baseline characteristics, better therapeutic strategy and prognosis of patients with concurrent malignancy need to be investigated. Long-term low-molecular-weight heparin (LMWH) is recommended for these patients, however, whether therapeutic strategy affects long-term prognosis remains unclear. MethodsIn this prospective study, acute symptomatic PE patients confirmed by imaging examinations, with/without malignancy, were enrolled and followed. Qanadli score was used to assess the embolic burden. The clinical endpoints included symptomatic recurrent venous thromboembolism (VTE), all-cause death and clinic relevant bleeding. ResultsIn the 627 patients enrolled, 92 patients had malignancy at baseline. The median follow-up period was 36months. The Qanadli score at baseline was lower in malignancy group than non-malignancy group (P=0.003). 48.9% of patients with malignancy died, while 11.4% of non-malignancy group died (P <0.001). Malignancy was a risk factor of death (HR 5.659, 95%CI 3.090-10.366, P <0.001). In malignancy group, 56 patients used long-term LMWH and 36 patients received oral vitamin K antagonist (VKA). The median survival time was 30months in LMWH group, significantly longer than 12.5months in VKA group (P=0.041). The mortality in the first 6months was lower in LMWH group than VKA group (19.6% vs. 41.7%, P=0.022). ConclusionsPE patients with malignancy had much higher incidence of all-cause death in spite of less embolic burden compared with patients without malignancy. Anticoagulation using long-term LMWH could prolong the survival time of PE patients with malignancy, and it was more effective than VKA.

RELATIONSHIP OF DIETARY SODIUM INTAKES WITH HOMA-IR AND BLOOD PRESSURE IN CHILDREN WITH MENTAL HEALTH CONDITIONS

BACKGROUND: Using data from AMPLIFY, a phase III trial comparing apixaban with conventional anticoagulant treatment in patients with venous thromboembolism (VTE), we performed subgroup analyses to compare the efficacy and safety of these regimens in patients with and without active cancer at baseline. Active cancer was defined as cancer that was diagnosed or treated within the past 6 months. METHODS: Patients with symptomatic VTE were randomized to a 6-month course of apixaban (10mg BID for 7 days followed by 5mg BID) or conventional treatment consisting of enoxaparin (1mg/kg BID for at least 5 days) followed by doseadjusted warfarin (target INR, 2-3). Cancer patients for whom long-term low-molecular-weight heparin (LMWH) was planned were excluded. The primary efficacy outcome was symptomatic VTE or VTE-related death. The intent-to-treat efficacy analysis included all randomized subjects with a nonmissing primary endpoint. The primary safety outcome was ISTH-defined major bleeding up to 2 days after stopping study drug in all randomized subjects who received at least one dose of study medication. All outcomes were adjudicated by an independent committee blinded to treatment assignment. RESULTS: Of 5395 patients randomized, 169 (3.1%) had active cancer. Baseline characteristics in these patients were similar between the two treatment groups. The median duration of treatment was 167 and 168 days in the apixaban and warfarin groups, respectively. In patients with active cancer at entry, recurrent VTE occurred in 3 of 81 (3.7%) patients in the apixaban group and in 5 of 78 (6.4%) in the warfarin group (relative risk [RR], 0.56; 95% CI, 0.132.37); major bleeding occurred in 2 of 87 (2.3%) and 4 of 80 (5.0%) patients, respectively (RR, 0.45; 95% CI, 0.082.46). In patients without cancer at entry, recurrent VTE occurred in 56 of 2528 (2.2%) and in 66 of 2557 (2.6%) patients in the apixaban and warfarin group, respectively (RR, 0.86; 95% CI, 0.60-1.22), whereas major bleeding occurred in 13 of 2589 (0.5%) and in 45 of 2609 (1.7%) patients in the apixaban and warfarin group, respectively (RR, 0.29; 95% CI, 0.16-0.54). CONCLUSION: Although the number of cancer patients was small, the results in this pre-specified subgroup are consistent with the overall findings and suggest that apixaban is as effective as conventional therapy in VTE patients with active cancer, and is associated with less bleeding. Additional studies are needed to compare the efficacy and safety of apixaban and LMWH for VTE treatment in cancer patients. Pfizer, BMS

PATTERNS AND PREDICTORS OF USE OF ANTICOAGULANTS FOR ACUTE VENOUS THROMBOEMBOLISM

Few studies have identified patterns and predictors of use of novel oral anticoagulants compared to warfarin for acute venous thromboembolism (VTE) in clinical practice. To describe the use of anticoagulants (AC) and to identify patient’s characteristics associated with the choice of rivaroxaban over warfarin for the treatment of VTE. A retrospective cohort was built from outpatient visits and inpatients records of hospitalisation between February 18, 2013, and September 18, 2013 (ie. starting 2 months following the availability of rivaroxaban for the treatment of VTE at our institution). This cohort includes new AC’s users treated in a tertiary care center for VTE. General characteristics and the type of AC prescribed was described using means and proportions and predictors of use of novel AC were analysed using two-tailed Student’s t-test for continuous variables and chi-square test for categorical variables. In an 8-months period, 261 patients were included; 67 (26%) had a diagnosis of cancer, 52 (20%) had at least one previous episode of VTE and 17 (7%) had confirm inherited thrombophilia. The median age was 65 years and 52% of the patients were women. The median body mass index was 28 (data were available for 199 patients) and the median length of stay was 8 days for hospitalisation (118 patients). Overall, 146 (56%) received warfarin, 43 (16%) received rivaroxaban and 72 (28%) received a prescription for long-term low molecular weight heparin at discharge. When compared to patients on warfarin, those who received rivaroxaban at discharge were younger (53 versus 63 years, p=0,001), had a higher mean creatinine clearance (93 versus 79 mL/min, p=0,002), were more likely to have an ambulatory visit rather than a hospitalisation (31% versus 60%, p<0,001) and were more likely to have a deep venous thrombosis than a pulmonary embolism (36% versus 58%, p=0,011). In new users of oral anticoagulants for the management of VTE, more subjects were on warfarin. Patients on rivaroxaban were younger and had a higher renal creatinine clearance. Rivaroxaban was more frequently prescribed in subjects who were not hosiptalized.

Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study.

BackgroundVenous thromboembolism is a common complication of cancer and its treatments. Treatment of cancer-associated thrombosis (CAT) differs from treatment of thrombosis in noncancer patients, requiring a daily injection of low-molecular-weight heparin (LMWH) for 6 months instead of an oral anticoagulant. Previous research suggested LMWH is an acceptable intervention in the treatment of CAT, yet clinical practice and therapeutic opportunities have changed in the decade since the study was conducted. Furthermore, in the previous study there was acknowledged selection bias in participant recruitment. There is increasing clinical use of the novel oral anticoagulants, although their efficacy and safety is yet to be demonstrated within the cancer population. The experience of patients receiving anticoagulation for CAT will inform future practice with respect to quality of life and adherence to anticoagulation therapy.AimTo explore the acceptability of long-term LMWH for the treatment of CAT in the contexts of living with cancer and quality of life.DesignQualitative study of cancer patients who had been receiving LMWH for at least 3 months for CAT was undertaken. Audiotaped semistructured interviews were conducted and transcribed. Thematic analysis was undertaken until theoretical saturation.Setting/participantsFourteen patients attending a palliative care or CAT clinic were interviewed. Participants had been receiving LMWH for a median 6 months.ResultsParticipants reported distressing symptoms associated with symptomatic CAT, which they rated as worse than their cancer experiences. LMWH was considered an acceptable intervention despite challenges of long-term injections. Several adaptive techniques were reported to optimize ongoing injections. Participants would only favor a novel oral anticoagulant if it was equivalent to LMWH in efficacy and safety.ConclusionAlthough LMWH remains an acceptable intervention for the treatment of CAT, its long-term use is associated with bruising and deterioration of injection sites. These are considered an acceptable trade-off against their strongly negative experiences of symptomatic venous thromboembolism.

Direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE), is a serious complication of cancer and its treatment. Patients with cancer have 4- to 7-fold higher risk of developing VTE than those without cancer [1]. Cancer patients with concurrent VTE have approximately 12% risk of bleeding during anticoagulation therapy and up to 25% annual risk of recurrent VTE [1]. The occurrence of VTE may also cause a delay or discontinuation of anti-cancer treatments, including chemotherapy and surgery [2]. Therefore, development of VTE in cancer patients has been associated with an increased risk of death [1]. In general, patients with VTE require anticoagulation therapy to prevent thrombus extension and death, which was largely associated with fatal PE, and to prevent recurrence in the long-term [2]. Traditionally, warfarin has been a common treatment strategy for patients with VTE; the use of warfarin in cancer patients, however, might be limited by complications of cancer and its treatment, including drug reactions, malnutrition, and the frequent need for dose adjustment [3]. As a result, low-molecular-weight-heparin (LMWH) was introduced as a suitable alternative anticoagulant because of few drug interactions and lack of requirement for routine laboratory monitoring; thus, it has been actively investigated in the treatment of cancer-associated VTE. A decade ago, the results of the phase III CLOT trial, which compared initial and maintenance therapy with dalteparin to warfarin therapy after initial dalteparin treatment in patients with cancer-associated VTE, were reported [4]. In this study, long-term dalteparin therapy was significantly associated with lower rates of 6-month cumulative incidence of recurrent VTE (9% vs. 17%) [4]. Since this study, LMWH has been the standard of care for initial and long-term therapy of patients with cancer-associated VTE. However, LMWH for long-term therapy requires a daily subcutaneous injection for cancer patients with VTE, which makes them feel uncomfortable. Thus, unmet needs are still present in the management of cancer-associated VTE.

Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients

Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients

Predicting Venous Thromboembolism Recurrence Risk in Patients with Cancer: A Validation Study

AbstractAbstract 394 Background:Long-term low molecular weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We have derived a clinical prediction rule that stratifies VTE recurrence risk in patients with cancer-associated VTE. The derivation model includes 4 independent predictors (sex, primary tumor site, stage and prior VTE). The score sum ranges between −3 and +3 points. Patients with a score ≤ 0 had low risk (≤4.5%) for recurrence and patients with a score above 1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized controlled trials comparing LMWH to warfarin for VTE treatment in cancer patients. In the current study we aim to externally validate our clinical prediction rule with an independent population of patients with cancer-associated VTE followed at the Thrombosis clinics of two tertiary Canadian centres. Methods:We conducted a retrospective cohort study of patients with cancer and VTE diagnosed and/or followed at the Thrombosis Clinic of the Victoria Hospital (London, Canada) from January 2006 to December 2010; and the Thrombosis Unit of the Ottawa Hospital (Ottawa, Canada) from January 2009 to December 2011. We included data from adult patients with active malignancy and objectively diagnosed acute pulmonary embolism (PE) or deep venous thrombosis (DVT) of the lower extremity (above knee), upper extremity and neck veins, or unusual site thrombosis. The primary outcome measure was VTE recurrence during the first six months of anticoagulation. Results:353 patients fulfilled our inclusion criteria and were included in the study. There were 149 males, and the overall population had a median age of 64 years (range: 18 – 95). One hundred and twenty-three patients had lower extremity DVT, 93 had PE and 57 had both. The remaining 80 patients had either upper extremity/neck DVT (n = 55) or unusual site thrombosis (n = 25). 77 patients had a prior history of VTE. The most common primary tumour site was gastrointestinal, followed by the lung. Of the 304 patients with solid tumours, 230 (75.7%%) had TNM greater than I.Two hundred and ninety-three (83.0%) patients were treated with longterm low molecular weight heparin (LMWH) only and 60 (17.0%) with warfarin (VKA). VTE recurrence occurred in 44 of 353 patients (12.4%). When we evaluated VTE recurrence risk per site, there was no significant difference: London 13 of 90 and Ottawa 31 of 263 [RR=1.23 (95%CI= 0.671 – 2.237; p=0. 507)]. In addition, there was no significant benefit with the use of LMWH (37 of 293) over VKA (7 of 60) in the risk of recurrence [RR=0.92 (95%CI= 0.433 – 1.973; p= 0.8379)]. When we applied our clinical prediction rule (Table 1) in the entire study population, recurrent VTE occurred in 12 of 204 (5.8%) patients stratified as low risk probability and in 32 of 149 (21.4%) patients stratified as high risk probability (Table 2). Conclusions:Our prediction rule has been adequately validated to now be used in prospective trials of treatment. Future trials evaluating novel treatment strategies for high risk patients are warranted.Table 1The Clinical prediction rule for risk stratification of VTE recurrence risk in patients with cancer- associated venous thrombosisPredictorPointsFemale1Lung cancer1Breast Cancer−1TNM$ Stage I−2Previous VTE**1Clinical ProbabilityLow risk of *rVTE (< or = 0)−3 to 0High risk of *rVTE (> or = 1)1 to 3*rVTE= recurrent venous thromboembolism.**VTE= venous thromboembolism.$TNM= tumour- node- metastasis classification of solid tumours.Table 2Results of the clinical prediction rule in the London-Ottawa retrospective studySum of PointsTotal Patients (n = 353)*rVTE (n = 44)Frequency of rVTE (%)-3100-24536.7-15658.9010243.91971616.52311342.038337.5Clinical ProbabilityLow Risk of rVTE (< or = 0)5.8%High Risk of rVTE (> or = 1)21.4%*rVTE= recurrent venous thromboembolism. Disclosures:No relevant conflicts of interest to declare.

Development of a Clinical Prediction Rule for Risk Stratification of Recurrent Venous Thromboembolism in Patients With Cancer-Associated Venous Thromboembolism

Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Compliance of recommendations with French clinical practice in the management of thromboembolism in patients with cancer: The CARMEN study.

1580 Background: Long-term treatment with low-molecular-weight heparin (LMWH) is recommended for treatment of venous thromboembolism (VTE) in cancer patients. Few data are available on compliance in this population. Our study measured whether the management of VTE in patients with cancer was consistent with French recommendations. Methods: Compliance with recommendations (CR+) was analysed according to malignancy and VTE from a 500-patient cross-sectional observational study run between May and October 2010. CR+ was defined as the compliance to initial 10-day treatment followed by long-term LMWH for at least 3 months, avoiding LMWH in patients with renal insufficiency (SRI). All inpatients with a diagnosis of cancer and VTE of less than 6 months were included in the study. Results: Of 500 patients included in 47 centers, 242 (49%) were male, 81 (18%) had local (T+), 83 (18%) had loco-regional (N+) and 287 (64%) had metastatic malignancies. Malignancies were gastro-intestinal (25%), gynaecologic (23%), pulmonary (21%), haematological (14%), urologic (10%) or other (8%). Twelve patients had SRI. Overall, treatment was CR+ in 289/500 patients (58% [95% CI 53%-62%]). Out of 12 patients with SRI only 3 (25%) were treated long-term with vitamin K antagonists (VKA), as usually recommended. Tumour site influenced CR+ (p=0.02). Treatment for haematological malignancy was poorly compliant with recommendations (32%) while patients with lung malignancy had the best compliance (68%). TNM stage and VTE location had no influence on treatment compliance. Conclusions: In French practice, treatment of cancer-related VTE is CR+ in 58% of cases. TNM stage and VTE location do not influence compliance which remains insufficient, especially in patients with haematological malignancy. [Table: see text]