Recurrent Venous Thromboembolism In Patients Research Articles

Predicting the risk of recurrent venous thromboembolism in patients with cancer: A prospective cohort study

BackgroundThe risk of recurrent venous thromboembolism (VTE) in cancer patients despite anticoagulant therapy is high. Clinical factors and pro-coagulant markers may identify high-risk patients and guide decisions about intensifying anticoagulation therapy. AimsTo evaluate whether serial measurements of pro-coagulant markers can identify patients at high risk of recurrent VTE. MethodsIn this multicenter, prospective cohort study, patients with active cancer and acute deep vein thrombosis or pulmonary embolism were enrolled. Patients received standard low-molecular-weight heparin therapy and were followed for 6 months. D-dimer and soluble P-selectin levels were measured at baseline and 1, 4, 5, 12, and 24 weeks post treatment initiation. The association between recurrent VTE and a previously developed risk score, baseline values of the biomarkers, and individual relative changes from baseline were assessed. ResultsWe enrolled 117 cancer patients (22% lung, 21% colorectal, 9% breast) with a mean age of 63 years; 62% had metastatic cancer. Eleven patients (9.4%) developed recurrent VTE, including two cases of fatal pulmonary embolism. VTE recurrence rates were 7.8% (95% CI, 3.1–18) in patients with a risk score of ≤0 points compared to 11% (95% CI, 5.2–20) for those with a score of ≥1 point (hazard ratio 1.3; 95% CI, 0.39–4.5). Baseline P-selectin levels but not D-dimer levels were significantly associated with a high risk of recurrence; the risk was four-fold higher in patients with elevated P-selectin levels than in those with normal levels (hazard ratio 4.0; 95% CI, 1.1–14). Changes in biomarker levels during treatment were not associated with recurrent VTE. ConclusionBaseline P-selectin but not D-dimer levels predict recurrent VTE and may be a valuable addition to clinical prediction rules to select patients for more intensive therapy or closer observation.

Management of Bleedings and Recurrent Venous Thromboembolism in Patients Receiving Vitamin K Antagonists

Management of Bleedings and Recurrent Venous Thromboembolism in Patients Receiving Vitamin K Antagonists

Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study

BackgroundThe optimal duration of oral anticoagulant therapy after a first, unprovoked venous thromboembolism is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. Risk stratification tools may assist in decision making. ObjectivesWe sought to determine the relationship between residual pulmonary embolism assessed by baseline ventilation-perfusion scan after completion of 5–7months of oral anticoagulant therapy and the risk of recurrent venous thromboembolism in patients with the first episode of unprovoked pulmonary embolism. MethodsWe conducted a multicentre prospective cohort study of participants with a first, unprovoked venous thromboembolism enrolled after the completion of 5–7months of oral anticoagulation therapy. The participants completed a mean 18-month follow-up. Participants with pulmonary embolism had baseline ventilation-perfusion scan before discontinuation of oral anticoagulant therapy and the percentage of vascular obstruction on baseline ventilation-perfusion scan was determined. During follow-up after discontinuation of oral anticoagulant therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated with reference to baseline imaging. Measurements and main resultsDuring follow-up, 24 of 239 (10.0%) participants with an index event of isolated pulmonary embolism or pulmonary embolism associated with deep vein thrombosis and central assessment of percentage of vascular obstruction on baseline ventilation-perfusion scan had confirmed recurrent venous thromboembolism. As compared to participants with no residual pulmonary embolism on baseline ventilation-perfusion scan, the hazard ratio for recurrent venous thromboembolism was 2.0 (95% CI 0.5–7.3) for participants with percentage of vascular obstruction of 0.1%–4.9%, 2.1 (95% CI 0.5–7.8) for participants with percentage vascular obstruction of 5.0%–9.9% and 5.3 (95% CI 1.8–15.4) for participants with percentage vascular obstruction greater than or equal to 10%. ConclusionsResidual pulmonary embolism assessed by pulmonary vascular obstruction on baseline ventilation-perfusion performed after 5–7months of oral anticoagulant therapy for the first episode of unprovoked pulmonary embolism was associated with a statistically significant higher risk of subsequent recurrent venous thromboembolism. Percentage of pulmonary vascular obstruction assessment by ventilation-perfusion scans maybe a useful tool to help guide the duration of oral anticoagulant therapy after a first unprovoked pulmonary embolism. Trial registrationRegistered at www.clinicaltrials.gov identifier: NCT00261014.

Outcomes after inferior vena cava filter placement in cancer patients diagnosed with pulmonary embolism: risk for recurrent venous thromboembolism.

Venous thromboembolism (VTE) is a common complication in cancer patients and anticoagulation (AC) remains the standard of care for treatment. Inferior vena cava (IVC) filters may also used to reduce the risk of pulmonary embolism, either alone or in addition to AC. Although widely used, data are limited on the safety and efficacy of IVC filters in cancer patients. We performed a retrospective review of outcomes after IVC filter insertion in a database of 1270 consecutive patients with cancer-associated pulmonary embolism (PE) at our institution between 2008 and 2009. Outcomes measured included rate of all recurrent VTE, recurrent PE, and overall survival within 12months. 317 (25%) of the 1270 patients with PE had IVC filters placed within 30days of the index PE event or prior to the index PE in the setting of prior DVT. Patients with IVC filters had markedly lower overall survival (7.3months) than the non-IVC filter patients (13.2months). Filter patients also had a lower rate of AC use at time of initial PE. There was a trend towards higher recurrent VTE in patients with IVC filters (11.9%) compared to non-filter patients (7.7%), but this was not significant (p = 0.086). The risk of recurrent PE was similar between the IVC filter cohort (3.5%) and non-filter group (3.5%, p = 0.99). Cancer patients receiving IVC filters had a similar risk of recurrent PE, but a trend towards more overall recurrent VTE. The filter patients had poorer overall survival, which may reflect a poorer cancer prognosis, and had greater contraindication to AC; therefore these patients likely had a higher inherent risk for recurrent VTE. A prospective study would be helpful for further clarification on the partial reduction in the recurrent PE risk by IVC filter placement in cancer patients.

Invited Commentary.

One of our strengths as a discipline has been our commitment to the long-term follow-up of patients on whom we have operated. There is no better example of this than the care provided to patients who have undergone aortic stent grafting, for which the limitations on follow-up are almost always the patient's compliance rather than the physician's engagement. However, we have come up short on the follow-up of the patients who have had inferior vena cava (IVC) filters placed, as proven by embarrassing low filter retrieval rates. This manuscript as well as many others 1 Winters J.P. Morris C.S. Holmes C.E. Lewis P. Bhave A.D. Najarian K.E. et al. A multidisciplinary quality improvement program increases the inferior vena cava filter retrieval rate. Vasc Med. 2017; 22: 51-56 Crossref PubMed Scopus (15) Google Scholar , 2 Davies R. Stanley J. Wickremesekera J. Khashram M. Retrieval rates of inferior vena cava (IVC) filters: are we retrieving enough?. N Z Med J. 2015; 128: 31-40 PubMed Google Scholar , 3 Sutphin P.D. Reis S.P. McKune A. Ravanzo M. Kalva S.P. Pillai A.K. Improving inferior vena cava filter retrieval rates with the define, measure, analyze, improve, control methodology. J Vasc Interv Radiol. 2015; 26: 491-498 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar , 4 Charlton-Ouw K.M. Leake S.S. Sola C.N. Sandhu H.K. Albarado R. Holcomb J.B. et al. Technical and financial feasibility of an inferior vena cava filter retrieval program at a level one trauma center. Ann Vasc Surg. 2015; 29: 84-89 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar , 5 Lucas D.J. Dunne J.R. Rodriguez C.J. Curry K.M. Elster E. Vicente D. et al. Dedicated tracking of patients with retrievable inferior vena cava filters improves retrieval rates. Am Surg. 2012; 78: 870-874 Crossref PubMed Google Scholar , 6 Kalina M. Bartley M. Cipolle M. Tinkoff G. Stevenson S. Fulda G. Improved removal rates for retrievable inferior vena cava filters with the use of a 'filter registry'. Am Surg. 2012; 78: 94-97 PubMed Google Scholar , 7 Simon T.E. Walker P.F. Daab L.J. White J.M. White P.W. A quality improvement project to improve inferior vena cava filter retrieval. J Vasc Surg Venous Lymphat Disord. 2017; 5: 42-46 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 8 Tao M.J. Montbriand J.M. Eisenberg N. Sniderman K.W. Roche-Nagle G. Temporary inferior vena cava filter indications, retrieval rates, and follow-up management at a multicenter tertiary care institution. J Vasc Surg. 2016; 64: 430-437 Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar , 9 Inagaki E. Farber A. Eslami M.H. Siracuse J.J. Rybin D.V. Sarosiek S. et al. Improving the retrieval rate of inferior vena cava filters with a multidisciplinary team approach. J Vasc Surg Venous Lymphat Disord. 2016; 4: 276-282 Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar , 10 Kalish J. Sloan M. Sarosiek S. Marks H. Moreira C. Hamburg N. et al. Tracking breeds success: improved retrieval rates of inferior vena cava filters with minimal dedication of resources. J Vasc Surg Venous Lymphat Disord. 2014; 2: 117 Abstract Full Text Full Text PDF PubMed Google Scholar demonstrates the fact that applying more energy to an administrative problem, the identification and follow-up of patients with removable IVC filters, provides better results in identifying those patients who are suitable candidates for filter removal. Impact of an inferior vena cava filter retrieval algorithm on filter retrieval rates in a cancer populationJournal of Vascular Surgery: Venous and Lymphatic DisordersVol. 5Issue 5PreviewOur primary purpose was to assess the impact of an inferior vena cava filter retrieval algorithm in a cancer population. Because cancer patients are at persistently elevated risk for development of venous thromboembolism (VTE), our secondary purpose was to assess the incidence of recurrent VTE in patients who underwent filter retrieval. Full-Text PDF

Low-molecular-weight heparins for the prevention of recurrent venous thromboembolism in patients with cancer: A systematic literature review of efficacy and cost-effectiveness.

BackgroundPatients with cancer have an elevated risk of venous thromboembolism. Importantly, patients with cancer, who have metastatic disease, renal insufficiency, or are receiving anticancer therapy, have an even higher risk of a recurrent event. Similarly, the risk of recurrent venous thromboembolism is higher than the risk of an initial event. To reduce the risk, extended duration of prophylaxis for up to six months with low-molecular-weight heparins such as dalteparin, enoxaparin, nadroparin, and tinzaparin is recommended by international guidelines. In this paper, the clinical and economic literature is reviewed to provide evidenced based recommendations based on clinical benefit and economic value.MethodsA systematic review of major databases was conducted from January 1996 to October 2016 for randomized controlled trials evaluating the four distinct low-molecular-weight heparins against a vitamin K antagonists control group for the prevention of recurrent venous thromboembolism in patients with active cancer. This was then followed by the application of the National Institute of Health and Clinical Excellence guidance to assess the quality of all trials that met the inclusion criteria. Finally, the cost-effectiveness literature supporting the value proposition of each product was reviewed.ResultsSix randomized trials met the inclusion criteria. There were one, two, and three trials that compared dalteparin, tinzaparin, and enoxaparin to a vitamin K antagonists control group. However, there were no trials for nadroparin in the setting of secondary venous thromboembolism prevention. In addition, only the dalteparin and one of the tinzaparin trials were of high quality and adequately powered. Of the two studies, only the dalteparin trial reported a statistically significant benefit in terms of venous thromboembolism absolute risk reduction when compared to a vitamin K antagonists control group (HR = 0.48; p = 0.002). In addition, there was robust pharmacoeconomic data from Canada, the Netherlands, France, and Austria supporting the cost-effectiveness of dalteparin for this indication. There were no such studies for any of the other agents.ConclusionsThe totality of high-quality clinical and cost-effectiveness data supports the use of dalteparin over other low-molecular-weight heparins for preventing recurrent venous thromboembolism in patients with cancer.

Impact of an inferior vena cava filter retrieval algorithm on filter retrieval rates in a cancer population.

Our primary purpose was to assess the impact of an inferior vena cava filter retrieval algorithm in a cancer population. Because cancer patients are at persistently elevated risk for development of venous thromboembolism (VTE), our secondary purpose was to assess the incidence of recurrent VTE in patients who underwent filter retrieval. Patients with malignant disease who had retrievable filters placed at a tertiary care cancer hospital from August 2010 to July 2014 were retrospectively studied. A filter retrieval algorithm was established in August 2012. Patients and referring physicians were contacted in the postintervention period when review of the medical record indicated that filter retrieval was clinically appropriate. Patients were classified into preintervention (August 2010-July 2012) and postintervention (August 2012-July 2014) study cohorts. Retrieval rates and clinical pathologic records were reviewed. Filter retrieval was attempted in 34 (17.4%) of 195 patients in the preintervention cohort and 66 (32.8%) of 201 patients in the postintervention cohort (P< .01). The median time to filter retrieval in the preintervention and postintervention cohorts was 60days (range, 20-428days) and 107days (range, 9-600days), respectively (P= .16). In the preintervention cohort, 49 of 195 (25.1%) patients were lost to follow-up compared with 24 of 201 (11.9%) patients in the postintervention cohort (P< .01). Survival was calculated from the date of filter placement to death, when available. The overall survival for patients whose filters were retrieved was longer compared with the overall survival for patients whose filters were not retrieved (P< .0001). Of the 80 patients who underwent successful filter retrieval, two patients (2.5%) suffered from recurrent VTE (n= 1 nonfatal pulmonary embolism; n= 1 deep venous thrombosis). Both patients were treated with anticoagulation without filter replacement. Inferior vena cava filter retrieval rates can be significantly increased in patients with malignant disease with a low rate (2.5%) of recurrent VTE after filter retrieval.

Occult cancer‐related first venous thromboembolism is associated with an increased risk of recurrent venous thromboembolism

Background Although venous thromboembolism (VTE) is associated with a high recurrence rate, the absolute recurrence rates for cancer-related VTE, particularly occult cancer, are not well known. Objectives To investigate the risk of VTE recurrence in patients with occult and overt cancer-related VTE. Methods Incident VTE events among participants of the first to sixth Tromsø surveys occurring in the period 1994-2012 were included. Occult cancer was defined as cancer diagnosed within a year following a VTE, and overt cancer was defined as cancer diagnosed within the 2 years before a VTE. Results Among 733 patients with incident VTE, 110 had overt cancer and 40 had occult cancer. There were 95 recurrent VTE events during a median of 3.2 years of follow-up. The 1-year cumulative incidence of VTE recurrence was 38.6% in subjects with occult cancer, 15.5% in subjects with overt cancer, and 3.8% in non-cancer subjects. The 1-year risk of recurrence was 12-fold (hazard ratio [HR] 12.4, 95% confidence interval [CI] 5.9-26.3) higher in subjects with occult cancer and four-fold (HR 4.3, 95% CI 2.0-9.2) higher in subjects with overt cancer than in non-cancer subjects. The occult cancers associated with VTE recurrence were typically located at prothrombotic sites (i.e. lung and gastrointestinal) and presented at advanced stages. The majority (69%) of recurrences in subjects with occult cancer occurred before or shortly after cancer diagnosis, and were therefore not treatment-related. Conclusion Our findings suggest that the increased risk of recurrence in patients with occult cancer is mainly attributable to the advanced cancers in these patients.

Survival and recurrent venous thromboembolism in patients with first proximal or isolated distal deep vein thrombosis and no pulmonary embolism

Background A few studies have focused on the risk of recurrence after first acute isolated distal deep vein thrombosis (IDDVT) compared with proximal DVT (PDVT), whereas the incremental risk of death has never been explored beyond the first 3 years after acute event. Methods Our single-center cohort study included patients with first symptomatic acute PDVT or IDDVT. Patients were excluded if they had concomitant pulmonary embolism (PE) or prior venous thromboembolism. The primary outcomes were symptomatic objectively diagnosed recurrent PDVT or PE and all-cause death. Results In total, 4759 records were screened and 831 subjects included: 202 had symptomatic IDDVT and 629 had PDVT. The median age was 66 years and 50.5% were women. A total of 125 patients had recurrent PDVT or PE during 3175 patient-years of follow-up: 109 events occurred after PDVT (17.3%) and 16 after IDDVT (7.9%). Annual recurrence rates were 4.5% (95% confidence interval [CI], 3.7-5.4%) and 2.0% (95% CI, 1.1-3.2%), respectively, for an adjusted hazard ratio (aHR) for IDDVT patients of 0.32 (95% CI, 0.19-0.55). Death occurred in 263 patients (31.6% [95% CI, 28.6-34.9%]) during 5469 patient-years of follow-up for an overall annual incidence rate of 4.8% (95% CI, 4.2-5.4%). The mortality rate was 33.5% (n = 211) in PDVT patients and 25.7% (n = 52) in IDDVT patients. The long-term hazard of death appeared lower for IDDVT patients (aHR, 0.75 [95% CI, 0.55-1.02]), especially after unprovoked events (aHR, 0.58 [95% CI, 0.26-1.31]). Conclusions Compared with PDVT, IDDVT patients were at a lower risk of recurrent VTE. The risk of death appeared lower after IDDVT during a median follow-up of 7.6 years.

Direct Oral Anticoagulants and Vitamin K Antagonists for Treatment of Deep Venous Thrombosis and Pulmonary Embolism in the Outpatient Setting: Comparative Economic Evaluation.

To date, there have been few economic evaluations, from a Canadian perspective, of direct oral anticoagulants (DOACs) for the prevention of recurrent venous thromboembolism (VTE) in patients with acute unprovoked VTE. As a result, there is a lack of consensus about which treatment strategy should be adopted in the clinical setting. To assess the cost-effectiveness of currently approved anti-coagulant options, in terms of cost per quality-adjusted life-year (QALY) gained, for the prevention of recurrent VTE in patients with unprovoked events managed on an outpatient basis. Microsoft Excel was used to develop a Markov model. Model parameters were determined using published literature, local hospital data, expert opinion, and chart review. The analysis considered the costs associated with pharmaceuticals, laboratory testing, hematologist fees, and treatment of recurrent VTE and major bleeding events. Effectiveness was measured in terms of QALYs, and incremental cost-effectiveness ratios (ICERs) were calculated. For treatment lasting 3 months, apixaban represented the most cost-effective DOAC relative to low-molecular-weight heparin (LMWH) + vitamin K antagonist, with an ICER of $7379.66. For 6 months of treatment, apixaban again represented the most cost-effective treatment, with an ICER of $84.08 per QALY gained, and this drug dominated all the other strategies at 12 months. For lifetime treatment, DOACs were unlikely to be cost-effective, given a maximum willingness to pay of $50 000 to $100 000 per QALY. In a probabilistic sensitivity analysis at 6 months, 46.4% of iterations resulted in apixaban having lower costs and better outcomes than LMWH + vitamin K antagonist, and 78.6% of iterations resulted in an ICER below $100 000. The findings of this study suggest that apixaban is likely cost-effective for treatment durations of 3, 6, and 12 months. However, for indefinite treatment, DOACs were unlikely to be cost-effective.

Preliminary Investigations Showing Venous Thromboembolism Recurrence in Patients with Residual Venous Obstruction in Singaporean Population.

This study aims to determine the association of residual venous obstruction (RVO) with recurrent venous thromboembolism (VTE). A retrospective cohort study was conducted determining if RVO on ultrasonography is associated with recurrent VTE in a Singaporean population. The subjects were identified from the Vascular Diagnostic Laboratory patients' record of Tan Tock Seng Hospital (TTSH), Singapore between 2008 and 2013. All the patients included had RVO after 3 months of anticoagulation. Data such as age, gender, race, thrombus location, etiology, history of malignancy, thrombophilia screen, treatment duration, and follow-up were recorded for analysis. Statistical analysis was performed using Stata/SE 13.1 (StataCorp LLC). The study was approved by the National Healthcare Group Domain Specific Review Board (DSRB), Singapore. Out of the 34 patients who had RVO, 6 (17.6%) developed VTE recurrence. Patients were treated with anticoagulation for a mean time of 24.5 months. The mean follow-up time for VTE recurrence was 25.4 months. Out of the six patients who had VTE recurrence, one had common iliac vein involvement, four had superficial femoral vein and common femoral vein involvement, zero had popliteal vein involvement, and one had calf veins involvement. There was a significant association between thrombophilia ( p = 0.0195) and malignancy ( p = 0.020) at inclusion with the risk of recurrent VTE. The presence of RVO after 3 months of anticoagulation is likely to increase the risk of VTE recurrence. Larger studies with RVO are needed to evaluate if there is an increased risk of VTE recurrence in the Asian population.

Dalteparin or vitamin K antagonists to prevent recurrent venous thromboembolism in cancer patients: a patient-level economic analysis for France and Austria.

International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146-53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR=0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates=3% vs. 17%; p=0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives. Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained. The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin=€2687 vs. VKA=€2012; France: dalteparin=€2053 vs. VKA=€1352: p<0.001). However, when the incremental costs were combined with the utility gain, dalteparin had a cost of €6600 and €4900 per QALY gained in Austria and France, respectively. The analyses in patients with renal impairment suggested an even better economic profile, with the cost per QALY gained being less than €4000 in both countries. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

Dalteparin versus vitamin K antagonists for the prevention of recurrent venous thromboembolism in patients with cancer and renal impairment: a Canadian pharmacoeconomic analysis.

BackgroundPatients with cancer are at increased risk of venous thromboembolism (VTE) and the risk is further elevated after a primary VTE. To reduce the risk of recurrent events, extended prophylaxis with vitamin K antagonists (VKA) is available for use. However, in a large randomized trial (Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer [CLOT]; Lee et al), extended duration dalteparin reduced the relative risk of recurrent VTE by 52% compared to VKA (p=0.002). A recent subgroup analysis of patients with moderate-to-severe renal impairment also revealed lower absolute VTE rates with dalteparin (3% vs. 17%; p=0.011). To measure the economic value of dalteparin as an alternative to VKA, a patient-level cost utility analysis was conducted from a Canadian perspective.MethodsResource use data captured during the CLOT trial were extracted and linked to 2015 Canadian unit cost estimates. Health state utilities were then measured using the Time-Trade-Off technique in 24 randomly selected members of the general Canadian public to estimate the gains in quality-adjusted life years (QALYs).ResultsFor the entire CLOT trial population (n=676), the dalteparin group had significantly higher mean costs compared to the VKA group ($Can5,771 vs. $Can2,569; p<0.001). However, the utility assessment revealed that 21 of 24 respondents (88%) selected dalteparin over VKA, with an associated gain of 0.14 (95% confidence interval [CI]: 0.10–0.18) QALYs. When the incremental cost of dalteparin was combined with the QALY gain, dalteparin had a cost of $Can23,100 (95% CI: $Can19,200–$Can25,800) per QALY gained. The analysis in patients with renal impairment suggested even better economic value with the cost per QALY gained being <$14,000.ConclusionExtended duration dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer, especially in those with renal impairment.

Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.

Population studies on the incidence of venous thromboembolism (VTE) in patients with active cancer are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The source population consisted of all patients in the UK Clinical Practice Research Datalink, with additional information on hospitalisation and cause of death, between 2001 and 2011. A cancer-related clinical diagnosis or therapy within the 90 days before or after a VTE constituted an active-cancer-associated VTE. Incidence rates of first VTE among patients with active cancer and incidence rates of recurrent VTE during the 10-year observational period after a first VTE event were estimated. Incidence rates of all-cause mortality and age- and gender-specific mortality were also calculated. There were 6,592 active-cancer-associated VTEs with a total of 112,738 cancer-associated person-years of observation. The incidence rate of first VTE in patients with active cancer was 5.8 (95 % confidence interval 5.7-6.0) per 100 person-years. A first VTE recurrence was observed in 591 patients. The overall incidence rate for recurrence was 9.6 (95 % confidence interval 8.8-10.4) per 100person-years, with a peak at 22.1 in the first six months. Recurrence rates were similar after initial pulmonary embolism and after initial deep-vein thrombosis. The mortality risk after VTE was considerable, with 64.5 % mortality after one year and 88.1 % after 10 years. VTE in patients with active cancer is common and associated with high recurrence and mortality rates. Efforts are needed to prevent VTE and reduce recurrence, especially in the first year after VTE diagnosis.

Overview of the Direct Oral Anticoagulants

ABSTRACT Over the past 6 decades, warfarin has proven efficacious in reducing stroke risk in patients with atrial fibrillation and reducing the risk of recurrent venous thromboembolism in patients with acute deep vein thrombosis or pulmonary embolism. However, there have been multiple challenges with using warfarin including delayed onset of action, need for bridging and monitoring as well as many drug-drug and drug-food interactions. Hence, long years of research have led to the development of direct oral anticoagulants. Of the 4 direct oral anticoagulants currently approved by the Food and Drug Administration, 1 is a direct thrombin inhibitor (dabigatran) and the other 3 are direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban). Direct oral anticoagulants have been found to be at least as effective as warfarin with fewer bleeding complications. This paper provides an overview of the evolution of anticoagulation therapies and an extensive literature review of the new direct oral anticoagulants.

Healthcare Resource Utilization and Costs Associated with Venous Thromboembolism Recurrence in Patients with Cancer

Introduction: Patients with cancer are not only at a high risk for developing primary but also recurrent venous thromboembolism (VTE). These events lead to increased burden of cancer management and healthcare costs. It was estimated that all-cause health care costs for cancer patients with VTE were $30,538/patient higher than in those without VTE (Khorana, 2013). To our knowledge, very little information exists on cost of VTE recurrence among cancer patients. The objective of this study was to analyze resource utilization and costs of patients with cancer experiencing a VTE recurrence using a large claims database.Methods: Medical and pharmacy claims from the Humana Database between 1/1/2013 and 05/31/2015 were analyzed. Newly diagnosed cancer patients with a first VTE diagnosis occurring after their first cancer diagnosis and with ≥1 dispensing of an anticoagulant agent within 7 days after their VTE diagnosis, were selected. Baseline characteristics were evaluated during the 6 month period prior to the index VTE. VTE recurrences were defined as hospitalizations with a primary diagnosis of VTE. Patients were classified into two groups: patients who experienced a VTE recurrence and patients who did not. Resource utilization and costs were evaluated for the entire follow up period, starting with the initiation of the anticoagulant therapy until whichever was earlier, end of eligibility or end of data. Healthcare resource utilization evaluated included number of hospitalizations, hospitalization days, emergency room (ER) visits, and outpatient visits. All-cause and VTE-related healthcare resource utilization was evaluated. Comparisons between patients with a VTE recurrence and patients without a VTE recurrence were performed using rate ratios (RR) and statistical differences between groups as well as 95% confidence intervals [95% CI] were calculated using Poisson regression models. All-cause and VTE-related healthcare costs were evaluated in per-patient-per-year (PPPY) and compared using mean cost difference.Results: A total of 2,428 newly diagnosed cancer patients who developed VTE and were treated with anticoagulants were identified. Of these, 413 (17.1%) experienced recurrent VTE during the follow up period. Patients who developed recurrent VTE and those who did not were similar in terms of age, gender, race, and region. No statistically significant differences between groups were observed in Charlson comorbidity index or in selected comorbidities during the 6 month baseline period. However, more patients with recurrent VTE recurrence had their index VTE documented during a hospitalization (61.3% vs. 55.4%, p=0.03). Patients with a VTE recurrence had significantly more ER and outpatient visits at baseline compared to those without recurrence, but no statistically significant difference was observed in baseline total healthcare costs ($29,352 vs. $27,955, p=0.44, respectively).The mean follow-up was similar between groups: 9.6 months for patients experiencing a VTE recurrence and 9.3 months for patients without a VTE recurrence (p=0.4059). Patients with a VTE recurrence had higher all-cause resource utilization rates (RRs; 95% CI) compared to patients without a VTE recurrence (hospitalization [2.37; 2.23 - 2.52], hospitalization days [2.64; 2.57 - 2.72], ER visits [1.62; 1.48 - 1.76], and outpatient visits [1.26; 1.24 - 1.28]). The rates of VTE-related hospitalization and VTE-related hospitalization days were close to $30,000 higher in patients with a VTE recurrence (Figure 1). The all-cause healthcare costs were $84,708 PPPY in patients with a VTE recurrence compared to $44,903 in patients without a VTE recurrence. The difference was mainly explained by lower VTE-related hospitalization costs (Figure 2).Conclusion: This real-world claims analysis showed that cancer patients with recurrent VTE consume significantly more healthcare resources. Total healthcare costs were nearly 2-fold higher in cohort with than in cohort without VTE recurrence. Close to 75% of the total cost difference was associated with VTE recurrence. VTE-related costs were ~4-fold higher in cohort with than in cohort without VTE recurrence. Reducing VTE recurrence in patients with cancer could lead to substantial healthcare cost savings. [Display omitted] [Display omitted] DisclosuresKhorana:Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. McCrae:Janssen: Membership on an entity’s Board of Directors or advisory committees. Milentijevic:Janssen Scientific Affairs: Employment, Equity Ownership. Fortier:Janssen Pharmaceuticals: Research Funding. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock.

Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study

In patients with pulmonary embolism, right ventricular dysfunction is associated with early mortality. The Hokusai-VTE study used N-terminal pro-brain natriuretic peptide (NT-proBNP) and right to left ventricular diameter ratio on CT as indicators of right ventricular dysfunction and reported that recurrent venous thromboembolism rates were lower with edoxaban than warfarin. The aim of the current study was to further explore the significance of right ventricular dysfunction and investigate potential explanations for the superiority of edoxaban-ie, differences in baseline clinical characteristics, duration of initial heparin treatment, bleeding rates, or quality of warfarin treatment. The Hokusai-VTE trial was a randomised, double-blind, event-driven non-inferiority trial in patients from centres in 37 countries that compared edoxaban with warfarin in the treatment of acute venous thromboembolism. Patients received treatment for at least 3 months and up to a maximum of 12 months. Patients were followed up for 12 months. Outcome data at 12 months was collected for all patients irrespective of treatment duration. This prespecified subgroup analysis focuses on the included patients with pulmonary embolism. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism defined as a composite of deep vein thrombosis or non-fatal or fatal pulmonary embolism at 12 months. Recurrence rates with edoxaban and warfarin were compared in patients with and without right ventricular dysfunction. In those with NT-proBNP concentrations of 500 pg/mL or higher, we compared baseline characteristics, duration of heparin treatment, and bleeding leading to study drug discontinuation in the edoxaban and warfarin groups. We also assessed quality of warfarin treatment. All analyses were done with the modified intention-to-treat population. The Hokusai-VTE trial is registered with ClinicalTrials.gov, number NCT00986154. Between Jan 28, 2010, and Oct 5, 2012, 8292 patients were enrolled from 439 centres, of whom 8240 received at least one dose of study drug. 3319 patients had pulmonary embolism. NT-proBNP was 500 pg/mL or higher in 465 (30%) of 1565 patients given edoxaban and in 507 (32%) of 1599 given warfarin. Recurrent venous thromboembolism occurred in 14 (3%) of 465 patients in the edoxaban group and 30 (6%) of 507 in the warfarin group (hazard ratio [HR] 0·50, 95% CI 0·26-0·94; p=0·033). The right to left ventricular diameter ratio was 0·9 or higher in 414 (44%) of 937 patients in the edoxaban group and 427 (45%) of 946 in the warfarin group. Recurrent venous thromboembolism occurred in 11 (3%) of 414 and 20 (5%) of 427 patients in the edoxaban and warfarin groups (HR 0·57, 95% CI 0·27-1·17; p=0·13). Baseline characteristics, duration of heparin treatment, and rates of bleeding leading to study drug discontinuation were similar in the edoxaban and warfarin groups and the quality of warfarin management was adequate for patients with NT-proBNP concentrations of 500 pg/mL or higher. Findings from our analysis suggest that edoxaban is more effective than warfarin in the treatment and prevention of recurrent venous thromboembolism in patients with pulmonary embolism and evidence of right ventricular dysfunction. Daiichi Sankyo.

Economic Analysis Comparing Dalteparin to Vitamin K Antagonists to Prevent Recurrent Venous Thromboembolism in Patients With Cancer Having Renal Impairment.

In a randomized trial (ie, Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer [CLOT]) that evaluated secondary prophylaxis of recurrent venous thromboembolism (VTE) in patients with cancer, dalteparin reduced the relative risk by 52% compared to oral vitamin K antagonists (VKAs; hazard ratio = 0.48, P = .002). A recent subgroup analysis in patients with moderate to severe renal impairment also revealed lower absolute VTE rates with dalteparin (3% vs 17%; P = .011). To measure the economic value of dalteparin in these populations, a pharmacoeconomic analysis was conducted from the Dutch health-care system perspective. Resource utilization data contained within the CLOT trial database were extracted and converted into direct cost estimates. Univariate analysis was then conducted to compare the total cost of therapy between patients randomized to dalteparin or VKA therapy. Health state utilities were then measured in 24 members of the general public using the time trade-off technique. When all of the cost components were combined for the entire population (n = 676), the dalteparin group had significantly higher overall costs than the VKA control group (dalteparin = €2375 vs VKA = €1724; P < .001). However, dalteparin was associated with a gain of 0.14 (95% confidence interval [CI]: 0.10-0.18) quality-adjusted life years (QALYs) over VKA. When the incremental cost was combined with the utility gain, dalteparin had a cost of €4,697 (95% CI: €3824-€4951) per QALY gained. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

Duration of anticoagulant therapy and VTE recurrence in patients with cancer.

10112Background: Anticoagulant therapy for minimum of 3-6 months is currently recommended for treatment of venous thromboembolism (VTE) in patients with cancer and clinical trials have not evaluate...

Management of venous thromboembolism in cancer patients: the economic burden of hospitalizations.

Venous thromboembolism (VTE) is one of the most frequent events associated with cancer, requiring hospitalization and generating additional healthcare costs. To date, no studies analyzing the additional costs resulting from VTE associated with cancer in France have been published. The objective of this study was to provide an estimation of the additional cost induced by VTE with cancer by analyzing hospital stays reported in the 2013 PMSI French Hospital Database ("Programme de Médicalisation des Systèmes d'Information", a national hospital administrative database) for four cancer types (breast, lung, hepatocellular carcinoma, and colon). The analysis is divided into three parts: a descriptive evaluation of hospitalizations for VTE with cancer, an analysis by severity level of diagnosis-related groups (DRG), and an estimation of the hospital costs based on the National Reference Costs (ENC). The French public ATIH ("Agence Technique de l'Information sur l'Hospitalisation", a national Agency for Data on Hospital Care) database was used. The critical approach of this study is based on analysis of the distribution of stays according to levels of severity of DRG. A total of 14,251 hospitalizations were analyzed combining VTE and cancer. Hospitalizations of the two highest levels of severity (levels 3 and 4) for VTE with cancer represented 81.7% of all hospitalizations in this population. Increased costs were seen for all four cancer types evaluated, with cost coefficients ranging from 1.34 to 2.01. For example, the average cost of lung cancer in cancer patients with VTE in the PMSI database was 7296 € versus 4647 € in the ATIH database. Cost coefficients were calculated, ranging from 1.34 in colon cancer, 1.50 for breast cancer, 1.57 in lung cancer, and 2.01 for hepatocellular carcinoma. As discussed in the article, the current costs are high. Better physician adherence to clinical practice guidelines could potentially reduce these costs by lowering the number of recurrent VTE in patients with cancer.