Recurrent Venous Thromboembolism In Patients Research Articles

PCN117 - Dalteparin Versus Vitamin K Antagonists for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer and Renal Impairment: Pharmacoeconomic Analysis of a Prospective Randomized Trial

PCN117 - Dalteparin Versus Vitamin K Antagonists for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer and Renal Impairment: Pharmacoeconomic Analysis of a Prospective Randomized Trial

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

OC-13 - Safe and effective use of direct oral anticoagulants (DOAC) versus conventional anticoagulation for the treatment of cancer-related venous thromboembolism

Cancer is a risk factor for the development of venous thromboembolism (VTE). The standard of care for the treatment of cancer-related VTE is a low molecular weight heparin (LMWH) formulation. The treatment for these events can be painful, lengthy, and expensive. The development of DOAC has created new options for the treatment of VTE. Data from a recent systematic review suggested that the safety and effectiveness of DOAC in patients with cancer is equivalent to that of traditional therapies. If equivalent to LMWH, the use of DOAC in the treatment of cancer-related VTE would reduce the risk of VTE recurrence while giving patients freedom from subcutaneous injections. Our primary aim was to determine the rate of VTE recurrence in patients on anticoagulation. Secondary aims were determination of the rate of anticoagulant-associated clinically relevant bleeding and VTE recurrence-free survival. We performed retrospective analysis (2014-2015) of the electronic medical records (EMR) of adult patients with cancer-related VTE treated with anticoagulation. We selected 122 patients for our final analysis according to the inclusion criteria. Demographic, laboratory, cancer diagnosis, and VTE diagnosis data were collected. We documented VTE recurrence as well as clinically relevant bleeding. Non-parametric statistical procedures were used to determine differences in variables associated with this study among the anticoagulant class groups, with a test significance level of 0.05. Among 122 patients, 89 (73%) were treated with LMWH, 26 (21%) were treated with DOAC, and 7 (6%) were treated with warfarin. The majority of VTE occurred in patients with advanced disease. The most common index event was pulmonary embolism (49%) followed by catheter-associated deep venous thrombosis (DVT) (24%). Recurrence of VTE occurred in 7.7% of patients receiving DOAC and 7.9% of patients receiving LMWH (P=NS). Major bleeding occurred more often with the use of DOAC (11.5%) than with LMWH (10.1%), but non-major bleeding was more common in patients receiving LMWH (9.0% versus 7.7%). These differences were not statistically significant. There was no mortality attributed to bleeding complications. The VTE recurrence-free survival rates were not statistically different among LMWH versus DOAC (Figure1). Recurrence of cancer-associated VTE is not uncommon, and the treatment of VTE has significant hemorrhagic risks. Our analysis suggests that there is no significant difference in the rate of VTE recurrence and anticoagulant-related bleeding when using oral DOACs versus LMWH. Further studies are needed to compare the safety and effectiveness of these methods of anticoagulation.

Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies.

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow‐up study

Several studies have shown that the family history of venous thromboembolism (FHVTE) is a predictor of first venous thromboembolism (VTE). However its role in recurrent VTE is still controversial. To investigate whether the presence of FHVTE is a risk factor for VTE recurrence in patients from a well-characterized Malmö thrombophilia study. VTE patients from the Malmö Thrombophilia Study were followed from discontinuation of warfarin treatment until diagnosis of VTE recurrence or to the end of the study (maximum follow-up 9.8 years). There were 127 events of VTE recurrence (12.2%) registered during the follow-up. Multivariate Cox regression analysis in patients with unprovoked first VTE showed that FHVTE was associated with higher risk of VTE recurrence (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-2.9) compared with patients with no FHVTE. Stratification of data according to thrombophilia status of patients showed that compared with the reference group (no FHVTE or thrombophilia), thrombophilia together with FHVTE was associated with a higher risk of VTE recurrence (HR 3.2, 95% CI 1.8-5.9) than thrombophilia alone (HR 1.8, 95% CI 1.02-3.2) independent of DVT location and duration of warfarin treatment. FHVTE was mainly an important risk factor of VTE recurrence in women (HR 3.1, 95% CI 1.6-5.8) but not in men (HR 1.1, 95% CI 0.6-2.2). Our results show that FHVTE is a risk factor for VTE recurrence in patients who had unprovoked first VTE. Furthermore, presence of FHVTE may be an additional risk factor of VTE recurrence in thrombophilia-positive patients.

Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis.

BackgroundPatients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended “life-long” anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a “weak provoking factor” there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.ObjectiveA systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.Data SourcesMEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.Study SelectionRandomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.Data ExtractionIndependent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.Data SynthesisSeven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11–0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69–3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40–1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.ConclusionsVKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients’ risk for recurrent PE as well as the patients’ values and preferences.

New insights into the mechanisms of action of aspirin and its use in the prevention and treatment of arterial and venous thromboembolism

The antithrombotic action of aspirin has long been recognized. Aspirin inhibits platelet function through irreversible inhibition of cyclooxygenase (COX) activity. Until recently, aspirin has been mainly used for primary and secondary prevention of arterial antithrombotic events. The aim of this study was to review the literature with regard to the various mechanisms of the newly discovered effects of aspirin in the prevention of the initiation and development of venous thrombosis. For this purpose, we used relevant data from the latest numerous scientific studies, including review articles, original research articles, double-blinded randomized controlled trials, a prospective combined analysis, a meta-analysis of randomized trials, evidence-based clinical practice guidelines, and multicenter studies. Aspirin is used in the prevention of venous thromboembolism (VTE), especially the prevention of recurrent VTE in patients with unprovoked VTE who were treated with vitamin K antagonists (VKAs) or with non-vitamin K antagonist oral anticoagulants (NOACs). Numerous studies have shown that aspirin reduces the rate of recurrent VTE in patients, following cessation of VKAs or NOACs. Furthermore, low doses of aspirin are suitable for long-term therapy in patients recovering from orthopedic or other surgeries. Aspirin is indicated for the primary and secondary prevention as well as the treatment of cardiovascular diseases, including acute coronary syndrome, myocardial infarction, peripheral artery disease, acute ischemic stroke, and transient ischemic attack (especially in atrial fibrillation or mechanical heart valves). Aspirin can prevent or treat recurrent unprovoked VTEs as well as VTEs occurring after various surgeries or in patients with malignant disease. Recent trials have suggested that the long-term use of low-dose aspirin is effective not only in the prevention and treatment of arterial thrombosis but also in the prevention and treatment of VTE. Compared with VKAs and NOACs, aspirin has a reduced risk of bleeding.

A Randomized Trial of Long-Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study

BackgroundPatients with cancer and VTE have a substantial risk of recurrent VTE. LMWH reduces the risk of symptomatic, recurrent VTE compared with warfarin and is recommended as the preferred anticoagulant by consensus guidelines. However, the evidence is based largely on a single, open-label randomized trial (CLOT; Lee et al NEJM 2003). Warfarin is still often used for the treatment of VTE in cancer patients worldwide.MethodsThe primary objective of this randomized, open-label, multicenter, Phase III trial (CATCH; NCT01130025) was to assess the efficacy of tinzaparin in preventing recurrent VTE in patients with active cancer and acute, symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Patients were randomized (stratified by geographic region, tumor characteristic [distant metastasis, no distant metastasis, hematological malignancy] and history of VTE) to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5-10 days overlapped and followed by dose-adjusted warfarin (target INR 2.0-3.0) for 6 months. The primary efficacy outcome was time to recurrent VTE verified by objective, standard imaging and blinded central adjudication; this was a composite primary endpoint that included symptomatic DVT and/or PE, incidental proximal DVT and/or PE and fatal PE. The primary safety endpoint was incidence of major bleeding. All patients were followed up to 6 months or death, whichever came sooner. Blinded central adjudication was also performed for all bleeding events and causes of death. A proportional hazards model for competing risks was applied to all randomized patients, treating all non-VTE-related deaths as competing events. An independent Data Safety Monitoring Board reviewed safety data at regular intervals.ResultsNine hundred patients were included from 165 sites in 32 countries across 5 continents. Of these, 449 were randomized to tinzaparin and 451 to warfarin. Mean age was 59 years (range 18-89); 59% female. A total of 77% of patients had a baseline ECOG performance status (PS) of 0-1 and 23% had a PS of 2. The most common primary tumor sites were gynecologic (23%), colorectal (13%), lung (12%), breast (9%); 10% had hematological malignancies. At the time of randomization, metastatic disease was present in 55% of patients and 44% had received prior cancer treatment (chemotherapy, surgery and/or radiation). Time-in-therapeutic range was 47% in the warfarin arm, with 27% above and 26% below the range. Over the 6-month trial period, 31 patients (6.9%) in the tinzaparin arm experienced recurrent VTE compared with 45 (10%) in the warfarin arm (hazard ratio [HR] 0.65 [95% CI 0.41-1.03; P=0.07]) (see figure). There were 2 patients with incidental VTE, both were in the warfarin arm. Symptomatic non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR 0.48 [95% CI 0.24-0.96]; P=0.04). Symptomatic non-fatal PE occurred in 3 patients in the tinzaparin arm and 2 in the warfarin arm; fatal PE occurred in 17 (3.8%) patients in each arm (HR 0.96 [95% CI 0.49-1.88]; P=0.90). There was no difference in the incidence of major bleeding events (n=13 [2.9%] in the tinzaparin arm and 12 [2.7%] in the warfarin arm), but significantly fewer patients experienced clinically relevant non-major bleeding with tinzaparin than warfarin (50 [11%] and 73 [16%] patients, respectively; P=0.03). No difference in mortality was seen with 6-month survival rates of 59% and 60%, respectively.ConclusionsIn cancer patients with symptomatic VTE, tinzaparin lowered the risk of recurrent VTE compared with warfarin, with a significant reduction in symptomatic DVT and clinically relevant non-major bleeding. No difference in major bleeding or overall mortality was observed. [Display omitted] DisclosuresLee:Bayer: Advisory Boards Other, Honoraria; Bristol-Myers Squibb: Advisory Boards, Advisory Boards Other, Research Funding; Boehringer Ingelheim: Honoraria; Daiichi-Sankyo: Advisory Boards, Advisory Boards Other; Eisai: Research Funding; LEO Pharma: Advisory Boards Other; Pfizer: Advisory Boards Other, Honoraria, Research Funding; Sanofi-Aventis: Advisory Boards, Advisory Boards Other; Avivia: Advisory Boards, Advisory Boards Other. Kamphuisen:LEO Pharma: Honoraria, Research Funding. Meyer:Bayer: Research Funding; Boehringer Ingelheim: Research Funding; LEO Pharma: Research Funding; Sanofi-Aventis: Research Funding. Janas:LEO Pharma: Employment. Jarner:LEO Pharma: Employment. Khorana:LEO Pharma: Honoraria, Research Funding.

Risk of Recurrent Venous Thromboembolism and Major Bleeding in Cancer-Associated Incidental Pulmonary Embolism Amongst Treated and Untreated Patients: A Pooled Analysis of 926 Patients

▪IntroductionIncidental pulmonary embolism (IPE) is defined as a pulmonary embolism diagnosed on a CT-scan performed for reasons other than a clinical suspicion of PE. Generally identified on staging scans, IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. In order to determine the outcome more accurately, and to identify clinical characteristics related to the prognosis, we pooled individual patient data from eleven observational studies and ongoing registries.MethodsA systematic literature search aiming to identify studies reporting on patients diagnosed with cancer-associated IPE was performed. Authors of selected studies were invited to participate. Incidence rates of objectively diagnosed symptomatic recurrent venous thromboembolism (VTE), major bleeding and mortality during 6-month follow-up were pooled. Individual patient data was collected to perform subgroup analyses, for which all patients were considered as one cohort. Hazard ratios (HR) were adjusted for age, sex and cancer stage.ResultsIndividual patient data of 926 cancer patients with IPE from 11 observational studies and ongoing registries were included (Table 1). The overall pooled 6-month risk of symptomatic recurrent VTE was 5.8% (95%CI 3.7-8.3), of major bleeding 4.7% (95%CI 3.0-6.8) and of mortality 37% (95%CI 28-47). The VTE recurrence risk was comparable in patients treated with VKA and LMWH with incidence rates of 6.4% (95%CI 2.2-12) and 6.2% (95%CI 3.5-9.6), HR 0.89 (95%CI 0.27-2.9). In contrast, this incidence rate was 12% (95%CI 4.7-23) in patients who were left untreated, HR 2.9 (95%CI 0.65-13; Figure 1). The risk of major bleeding was significantly higher in patients treated with VKA compared to those treated with LMWH, 13% (95%CI 6.4-20) versus 3.9% (95%CI 2.3-5.9), HR of 3.2 (95%CI 1.4-7.4) (Figure 2). The 6-month mortality was 37% (95%CI 29-44) in patients treated with LMWH, 28% (95%CI 18-40) in those treated with VKA and 47% (95%CI 28-66) amongst untreated patients. The all-cause mortality at 6 months was significantly higher for patients with a central thrombus (either central or lobar) compared to those with a more peripheral IPE (either segmental or subsegmental); 42% (95%CI 33-52) versus 30% (95%CI 25-36, HR 1.8 (95%CI 1.4-2.3).ConclusionsThe most important finding of this study is the 12% 6-month risk of symptomatic recurrent VTE in patients with cancer-associated IPE who did not receive anticoagulant treatment, which is more than double the risk of patients who were anticoagulated. These numbers recall the effect size of anticoagulants used in symptomatic PE and support the judicious initiation of anticoagulant treatment in cancer-associated IPE. The association between more centrally-located thrombi and mortality following IPE is a new finding that parallels outcomes for symptomatic PE, and one which may further support similar management. Regarding the choice of anticoagulant, VKA were associated with a significantly higher risk of major bleeding than LMWH, with a comparable risk of recurrent VTE. The findings of this observational study should be preferably confirmed in a randomized trial. [Display omitted] [Display omitted] Abstract 590. Table 1:Baseline characteristicsTreatmentAll patientsn=926(100%)LMWHn=732(79%)VKAn=100(11%)No treatmentn=53(6%)Other treatmentn=41(4%)Mean age (SD)65 (12)64 (12)68 (12)65 (14)68 (13)Male sex, n (%)491 (53)378 (52)60 (60)31 (58)22 (54)Cancer stage, n (%)Metastatic501 (54)400 (55)56 (56)33 (62)12 (29)Non-metastatic192 (21)143 (20)34 (34)12 (23)3 (7.3)Unspecified233 (25)189 (26)10 (10)8 (15)26 (63)Cancer type, n (%)Lung176 (19)135 (18)16 (16)18 (34)7 (17)Colorectal185 (20)150 (20)20 (20)9 (17)6 (15)Other gastrointestinal187 (20)147 (20)15 (15)13 (25)12 (29)Breast65 (7.0)52 (7.1)10 (10)1 (1.9)2 (4.9)Gynaecological64 (6.9)56 (7.7)5 (5.0)0 (0)3 (7.3)Other206 (22)155 (21)31 (31)10 (19)10 (24)Haematological43 (4.6)37 (5.1)3 (3.0)2 (3.8)1 (2.4)Largest artery involved, n (%)Central292 (32)230 (31)30 (30)11 (21)21 (51)Peripheral495 (53)395 (54)62 (62)29 (55)9 (22)Unspecified139 (15)107 (15)8 (8.0)13 (25)11 (27) DisclosuresNo relevant conflicts of interest to declare.

Outcome of central venous catheter associated upper extremity deep vein thrombosis in cancer patients

IntroductionData on efficacy and safety of using low molecular weight heparin in cancer patients with catheter-related upper extremity deep vein thrombosis is scarce and the risk of recurrent venous thromboembolism after discontinuation of anticoagulation is unknown. Material and methodsWe conducted a retrospective cohort study including consecutive cancer outpatients assessed for the management of symptomatic central venous catheter-associated proximal upper extremity deep vein thrombosis. ResultsOf 99 included patients, 89 were treated with one month of full therapeutic weight-adjusted dose of low molecular weight heparin followed by an intermediate dose. Median duration of anticoagulation was 124days (range 40 to 1849). No recurrent venous thromboembolism and two major bleeding episodes occurred during the first 3months of treatment. Eighty patients were followed-up after anticoagulation discontinuation for a median of 632days (range 6 to 2495). Central venous line was pulled in all patients in remission and in 26 of the 29 patients (89.6%) with active cancer. Five recurrences were observed during follow-up. The cumulative probability of recurrent venous thromboembolism was higher in patients whose cancer was active at the time of anticoagulation discontinuation as compared with those in remission (22.2% (95% CI: 0 to 40.6) vs. 2.3% (95% CI: 0 to 6.7)). ConclusionThe risk of venous thromboembolism recurrence in patients whose central venous catheter has been pulled out and cancer is in remission appears low following anticoagulation discontinuation and after a minimum of 3months of full/intermediate dose.

Edoxaban: a new oral direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders

Anticoagulants have a key role in the treatment of arterial and venous thromboembolic disorders. The recently introduced novel oral anticoagulants target a single coagulation factor (factor Xa or thrombin) and address several of the limitations associated with traditional agents. Edoxaban is an oral direct factor Xa inhibitor that inhibits free and clot bound factor Xa and has been investigated in an extensive clinical development program. This article provides an overview of the mechanism of action, pharmacokinetics and pharmacodynamics of edoxaban. Phase III studies have evaluated edoxaban versus conventional therapy to prevent stroke in patients with atrial fibrillation (ENGAGE AF-TIMI 48) and in the treatment and prevention of recurrent venous thromboembolism in patients with deep vein thrombosis and/or pulmonary embolism (Hokusai-VTE).

Weekly risk of venous thromboembolism recurrence in patients receiving oral anticoagulants

Background:Data is currently lacking in evaluating the weekly rates of recurrent venous thromboembolism (VTE) among patients receiving anticoagulants.Objective:To quantify the risk of VTE recurrence during the first 12 weeks after an index VTE event.Methods:Healthcare claims from Truven Health Analytics MarketScan database from January 2007 to June 2012 were analyzed. Adult patients with ≥1 diagnosis of VTE, ≥1 anticoagulant prescription dispensed within 7 days of the index VTE hospitalization discharge or outpatient/emergency room (ER) visit (index date), and a proportion of days covered ≥0.7 on the anticoagulant therapy during the 12 weeks post-discharge were included. The weekly risk of VTE recurrence was evaluated with the hazard function using the life-table method.Results:A total of 105,682 patients with a VTE were included. Mean age was 59 years and 49% were female. The risk of VTE recurrence was at its highest during the first and second weeks, at 0.78% and 0.83%, respectively. The risk remained high during Weeks 3, 4, and 5 with risks of VTE recurrence of 0.63%, 0.52%, and 0.39%, respectively. The risk of VTE recurrence stabilized around Week 7, with risks of 0.26%, 0.22%, 0.20%, 0.25%, 0.23%, and 0.23% for Weeks 7, 8, 9, 10, 11 and 12, respectively.Limitations:Claims data may have contained inaccuracies. During hospitalizations it was not possible to assess anticoagulant use or a VTE recurrence occurring in the same hospitalization as the index VTE event.Conclusion:This analysis suggests that the risk of VTE recurrence remains high in the early weeks after an index VTE among patients receiving anticoagulants.

Transforming growth factor (TGF)-β levels and unprovoked recurrent venous thromboembolism

Prediction of recurrence in patients with unprovoked venous thromboembolism (VTE) remains a challenge. Studies of atherosclerosis suggest a protective role of transforming growth factor (TGF)-β. However, the role of TGF-β has not been studied in VTE. The aim of this study was to investigate TGF-β as a predictive marker of recurrent VTE in patients with a first episode of unprovoked VTE. Patients in the Malmö Thrombophilia Study (MATS) were followed after the discontinuation of anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study in December 2008 (mean ± SD 38.5 months ± 27). Among patients with a first episode of unprovoked VTE, we identified 42 patients with recurrent VTE during the follow-up period. Two age- and sex-matched control subjects without recurrent VTE were selected for each patient (n = 84). Plasma levels of the three isoforms of TGF-β (TGF-β1, TGF-β2 and TGF-β3) were quantified simultaneously by TGF-β 3-plex immunoassay. Compared to controls, plasma levels of TGF-β1 and TGF-β2 were significantly lower in patients with recurrent VTE (p < 0.05), whereas no difference was found for TGF-β3. In a multivariate Cox regression analyses, adjusted for inherited thrombophilia, age, sex and BMI, low levels of TGF-β1 [hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.1-4.3; p = 0.02] and TGF-β2 (HR = 2.4, 95% CI 1.2-4.7; p = 0.01) were independently associated with a higher risk of recurrent VTE. We propose TGF-β1 and TGF-β2 as potential predictive markers for recurrence in patients with unprovoked VTE.

Statin Use Was Associated With a Non-Significant Reduction In The Observed Incidence Of Recurrent VTE In Einstein-DVT and Einstein-PE

BackgroundSeveral observational studies in patients at high risk of arterial vascular disease have shown that statin use is associated with a decreased risk of venous thromboembolism (VTE). A recent meta-analysis showed that the odds ratio for a first venous thromboembolic event for statin users was 0.89 (95% confidence interval [CI], 0.78–1.01) compared with non-users (Rahmini K, et al. PLoS Med 2012;9: e1001310 doi:10.1371/journal.pmed.1001310). ObjectiveTo evaluate the risk of recurrent VTE in patients with VTE treated with an anticoagulant (rivaroxaban or enoxaparin/vitamin K antagonist [VKA]) in relation to the concomitant use of statin therapy in the EINSTEIN-DVT and EINSTEIN-PE studies. MeasurementsIncidence densities of symptomatic recurrent VTE and major bleeding were expressed per 100 patient-years of exposure (or not) to statins. A Cox proportional hazards model was employed, with statin use as a time-dependent variable, for each treatment group (rivaroxaban vs enoxaparin/VKA) and adjusted for aspirin use, age, body mass index, cardiac disorders, gender, and creatinine clearance at baseline. ResultsA total of 1509 (18%) of the 8240 patients included in EINSTEIN-DVT and EINSTEIN-PE used statins during the course of the studies. Statin users were more likely to have cardiovascular disorders (31% vs 10%) and also used aspirin more often (26% vs 5%). During statin/rivaroxaban treatment, recurrent VTE occurred with an incidence of 2.0 per 100 patient-years versus 3.6 during non-statin-use (adjusted hazard ratio [HR], 0.62; 95% CI, 0.29–1.32). During statin/enoxaparin/VKA use, recurrent VTE occurred at an incidence of 3.2 per 100 patient-years versus 4.0 during non-statin-use (adjusted HR, 0.89; 95% CI, 0.47–1.69). Major bleeding during statin/rivaroxaban treatment occurred at an incidence of 2.2 per 100 patient-years versus 1.6 during non-statin-use (adjusted HR, 0.92; 95% CI, 0.43–1.98). During statin/enoxaparin/VKA treatment, the rate of major bleeding was 3.7 per 100 patient-years compared with 3.0 during non-statin-use (adjusted HR, 0.69; 95% CI, 0.36–1.32). Due to the adjustments in the Cox regression model the direction of these hazard ratios are in contrast to the crude comparison of rates by patient-years. This is largely because, in general, statin users are older and most of the major bleeding events in statin users occur in the ≥60 years age group. LimitationsThe study comprised a post-hoc analysis of data collected in two randomized clinical trials. Because the analyses were not a comparison of randomized groups, residual confounding is possible. ConclusionsA modest, but not statistically significant, reduction in recurrent VTE was observed with statin use in patients treated for VTE. This reduction was similar in patients receiving enoxaparin/VKA or rivaroxaban therapy. Disclosures:Gebel:Bayer HealthCare AG: Employment, Equity Ownership. Prins:Bayer HealthCare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; sanofi-aventis: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria, Research Funding; ThromboGenics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Lensing:Bayer HealthCare: Employment.

T150 Treatment of pulmonary embolism in active malignancy - prescribing practices amongst physicians

IntroductionPulmonary embolism (PE) is a common complication of malignancy. NICE guidance for the treatment of venous thromboembolism (VTE) issued in June 2012 recommended that those with active cancer and confirmed...

CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients

BackgroundLow-molecular-weight heparin (LMWH) is recommended and commonly used for extended treatment of cancer-associated thrombosis (CAT), but its superiority over warfarin has been demonstrated in only one randomised study. We report here the rationale, design and a priori analysis plans of Comparison of Acute Treatments in Cancer Haemostasis (CATCH; NCT01130025), a multinational, Phase III, open-label, randomised controlled trial comparing tinzaparin with warfarin for extended treatment of CAT.Methods/DesignThe primary objective is to assess the efficacy of tinzaparin in preventing recurrent venous thromboembolism (VTE) in patients with active cancer and acute, symptomatic proximal deep vein thrombosis and/or pulmonary embolism. The secondary objectives are to determine: safety of tinzaparin given over 6 months; clinical and laboratory markers for recurrent VTE and/or major bleeding; 6-month overall mortality; incidence and severity of post-thrombotic syndrome; patient-reported quality of life; and healthcare resource utilisation. Nine hundred patients are randomised to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5–10 days and dose-adjusted warfarin (target INR 2.0–3.0) for 6 months. The primary composite outcome is time to recurrent VTE, including incidental VTE and fatal pulmonary embolism. All patients are followed up to 6 months or death, whichever comes sooner. Blinded adjudication will be performed for all reported VTE, bleeding events and causes of death. Efficacy will be analysed using centrally adjudicated results of all patients according to intention-to-treat analysis. An independent Data Safety Monitoring Board is reviewing data at regular intervals and an interim analysis is planned after 450 patients have completed the study.DiscussionThe results will add significantly to the knowledge of the efficacy, safety and cost effectiveness of tinzaparin in the prevention of recurrent VTE in patients with cancer and thrombosis. Prospective data will emerge on the clinical significance of incidental VTE and risk stratification in patients with CAT. Results on post-thrombotic syndrome, quality of life and healthcare resource utilisation will inform decision makers on how to secure better patient care. If tinzaparin is shown to be more effective than warfarin, CATCH will provide valuable confirmatory data to support the use of the LMWH tinzaparin for extended treatment of CAT.

Abstract 52: Association of Heparin Lead-in Therapy and Recurrence in the Treatment of Venous Thromboembolism

Background: Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Anticoagulant treatment significantly decreases the risk of recurrent VTE events and is typically initiated with the administration of a heparin therapy along with warfarin followed by warfarin treatment alone. The objective of this study was to assess the association between heparin lead-in therapy and VTE recurrence in patients receiving warfarin. Methods: Data from adult patients who had a VTE diagnosis in a large claims database (period 2005 - 2011), a warfarin claim within 30 days and continuous eligibility for at least 12 months pre/post first (index) diagnosis, were analyzed. Patients with atrial fibrillation, VTE, or treatment with warfarin therapy prior to the index date were excluded. Patients were classified into 4 cohorts: 1) Outpatient DVT; 2) Outpatient PE; 3) Inpatient DVT; 4) Inpatient PE. Inpatient cohort patients had an index inpatient VTE claim or had an inpatient VTE claim within 7 days of an index outpatient VTE claim. Outpatient cohort patients were required to have another outpatient VTE claim within 7 days of their index claim. Patients with both DVT and PE claims were included in the PE cohorts. Recurrent VTE was defined as the presence of an inpatient VTE claim within 365 days from the index date. Heparin use was identified by a UFH/LMWH pharmacy claim within 7 days of the outpatient index date or discharge from an inpatient VTE index event. Cox proportional hazard models adjusting for age, gender, health insurance type and baseline Elixhauser comorbidities were used. Results: A total of 39,424 patients met study criteria. Mean (SD) age was 59.8 (15.6) years and 50.6% (19,946/39,424) were female. Most patients (72.0%; 28,388/39,424) had an index inpatient event with a mean (SD) LOS=5.4 (4.1) days. Outpatient DVT/PE patients who used heparin had significantly lower rates of VTE recurrence vs. those who did not ( P &lt;0.05). Post-discharge heparin use was not associated with VTE recurrence rates within inpatient cohorts. Conclusion: The use of heparin lead-in therapy can significantly reduce VTE recurrence in the Outpatient VTE cohorts. Due to the lack of inpatient drug use data to identify heparin use in this claims database, additional studies are needed to confirm our Inpatient cohort results.

Non-OO blood type influences the risk of recurrent venous thromboembolism

The role of ABO blood type as a risk factor for recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who complete oral anticoagulation therapy is unknown. The aim of this study was to determine if non-OO blood type is a risk factor for recurrent VTE in patients with a first unprovoked VTE who completed 5-7 months of anticoagulant therapy. In an ongoing cohort study of patients with unprovoked VTE who discontinued oral anticoagulation after 5-7 months of therapy, six single nucleotide polymorphisms sites were tested to determine ABO blood type using banked DNA. The main outcome was objectively proven recurrent VTE. Mean follow-up for the cohort was 4.19 years (SD 2.16). During 1,553 patient-years of follow-up, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% CI 5.3-7.7) compared to 14 events during 560 patient years of follow-up in 129 OO patients (2.5 per 100 patient years; 95% CI 1.2-3.7), the adjusted hazard ratio was 1.98 (1.2-3.8). In conclusion, non-OO blood type is associated with a statistically significant and clinically relevant increased risk of recurrent VTE following discontinuation of anticoagulant therapy for a first episode of unprovoked VTE.

Outpatient Treatment of Symptomatic Pulmonary Embolism: A Systematic Review and Meta-Analysis

AbstractAbstract 361 Background:Patients with deep vein thrombus (DVT) can safely be treated as outpatients using subcutaneous low molecular weight heparin (LMWH). However the role of outpatient treatment in patients diagnosed with a pulmonary embolism (PE) is controversial. This practice is not accepted in many centers and majority of patients are still admitted to the hospital for observation. Clinicians are reluctant to discharge patients due to insufficient data supporting the safety of outpatient management of PE. Purpose:To determine the safety of outpatient treatment of acute symptomatic PE and the outcomes associated with outpatient management of PE including venous thromboembolism (VTE) recurrence, major bleeding, fatal PE, fatal intracranial hemorrhage (ICH), and overall mortality. Methods:A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to June 2012. We included randomized controlled trials (RCTs) and prospective cohort studies. We calculated the pooled proportions for the different outcomes at 3-months of follow-up. Ninety-five percent confidence intervals (95% CI) were calculated for each rate using the averaged, inverse variance-weighted estimates from each study. Results:Thirteen studies met all the inclusion criteria (3 RCTs and 10 prospective cohort studies). A total of 2458 patients were included in the systematic review. Different risk stratification methods were used to identify low risk patients with PE such as the pulmonary embolism severity index (PESI), the Geneva prognostic score, clinical gestalt and/or laboratory markers. The risk of recurrent VTE in patients with PE managed as outpatients was 1.64% (95% CI 0.69 – 3.0%; I2: 70.7%) during the 3 months follow-up period. The rate of fatal PE was 0.70% (95% CI 0.14 – 1. 7%; I2: 72.6%). The rates of major bleeding and ICH were 1.14% (95% CI 0.35 – 2.34%; I2: 72.8%) and 0.29% (95% CI 0.06– 0.68%; I2: 0%), respectively. The overall mortality rate was 2.3% (95% CI 0.41 – 5.7%; I-square: 92.8%). The I2 was moderate to high for most proportions, likely due to difference in the baseline characteristics (e.g. the inclusion of cancer patients in some studies). Conclusion:Independent of the risk stratification methods used, the rate of adverse events associated with outpatient PE treatment seems low. Based on our systematic review and pooled meta-analysis, numerous patients with acute PE can safely be treated as outpatients. [Display omitted] Proportion meta-analysis showing the risk of recurrent VTE in patients with PE managed as outpatients for a 3 month follow up period. Disclosures:No relevant conflicts of interest to declare.

Clinical Predictors of Confirmed Venous Thromboembolism in Patients with a Suspected Recurrent Venous Thromboembolism: A Retrospective Study of the Reverse I Cohort

AbstractAbstract 1153 Background:Many clinical decision rules (CDR), such as the Wells models for deep vein thrombosis of the legs (DVT) and pulmonary embolism (PE), have been established for patients with suspected first venous thromboembolism (VTE). However these rules may have limitations for patients with suspected recurrent VTE. First, patients with suspected PE and a history of VTE have their diagnosis more likely confirmed than patients with a suspected PE without a history of VTE (40.3 vs. 20.6%) (Le Gal G et al. Arch Intern Med, 2006), suggesting a different pre-test probability. Furthermore, patients who had a previous pulmonary embolism often have complaints of chronic dyspnea (Klok FA et al. Eur J Intern Med, 2008), which could complicate the risk estimation of recurrent PE. A similar scenario arises for patients who suffered a DVT, as 30–50% of patients will show signs and symptoms of post-thrombotic syndrome (PTS) following a deep vein thrombosis (Kahn SR. Curr Opin Pulm Med, 2006). In addition, the value of D-dimer testing is still uncertain in patients with suspected recurrent VTE. Finally, imaging has limitations, as residual thrombosis may be present and may be misdiagnosed as an acute recurrent event. Hence, because pre-test probability, laboratory testing and diagnostic imaging performances differ in patients with a suspected recurrent VTE, a different approach may be needed for effective management of these patients.Our objective was to study clinical predictors for the diagnosis of recurrent VTE in patients with a history of VTE. Methods:The REVERSE I study enrolled patients with a first unprovoked, objectively proven VTE (Rodger M et al. CMAJ, 2008). Each patient in the REVERSE I cohort that had a suspected recurrent VTE during follow-up was screened for eligibility. Only first adjudicated suspected recurrent events were studied. All these events were blindly adjudicated by an independent committee. Potential clinical predictors of recurrent VTE consisted of clinical predictors collected at the baseline visit (5–7 months after the unprovoked event), and of information collected in physicians’ clinical notes, laboratory or imaging results at the time of the suspected recurrent VTE.The predictive value of each predictor was determined by the Chi-square test for nominal data and the unpaired 2-tailed T-test for continuous data. Results:In the REVERSE I cohort, out of the 646 patients who were followed, 402 patients had a suspected recurrent VTE within a mean of 20.2 months (range: 0 – 97 months) of follow-up. After screening, 376 patients were enrolled in our study: 52.7 % of patients were males, and the mean age was 53.1 years (± 17.5). Among all suspected recurrent VTE events, male gender and a positive d-dimer result at the time of suspected recurrent VTE (p < 0.01), as well as symptoms occurring for 10 days or less at the time of presentation (p < 0.05) were in favor of a recurrent VTE diagnosis. In addition, mean age was higher in patients with a confirmed recurrent VTE (p < 0.05).In patients with suspected DVT, the presence of leg swelling was in favor of a confirmed diagnosis (p < 0.01), while leg pain was not associated with a higher rate of confirmed DVT. A suspected DVT in the same leg as the previous event seemed less likely to have a confirmed diagnosis of recurrent DVT. However this trend was not statistically significant.In patients with suspected PE, mean oxygen saturation was lower among patients with a new PE diagnosis (p < 0.05). Chest pain and shortness of breath were not important predictors.Finally, in the case of a suspected DVT and PE event, shortness of breath was a significant predictor (p < 0.05) for the diagnosis of recurrent VTE. Conclusion:This is the first study to show that predictors for the diagnosis of a recurrent VTE may be different than predictors for the diagnosis of a first VTE. For instance, our results show that male gender is not only a risk factor for recurrent VTE (McRae S et al. Lancet, 2006), but is also an important predictor for confirmed VTE among patients with suspected recurrent VTE, while none of the existing CDRs take this in consideration. A CDR specific to patients with a history of VTE may be needed for better management of these patients. Disclosures:Le Gal:Bayer, bioMérieux, GSK, Leo Pharma, Sanofi Aventis: Honoraria.