Thrombosis Research 130 (2012) Contents lists available at SciVerse ScienceDirect. Thrombosis Research

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1 Thrombosis Research 130 (2012) Contents lists available at SciVerse ScienceDirect Thrombosis Research journal homepage: Regular Article Long-term death and recurrence in patients with acute venous thromboembolism: The MASTER registry Melina Verso a,, Giancarlo Agnelli a, Walter Ageno b, Davide Imberti c, Marco Moia d, Gualtiero Palareti e, Riccardo Pistelli f, Valeria Cantone g and for the MASTER investigators a Division of Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Perugia, Italy b Department of Clinical Medicine, University of Insubria, Varese, Italy c Unit of Internal Medicine, Hospital of Piacenza, Piacenza, Italy d Haemophilia and Thrombosis Center Bianchi Bonomi, IRCCS Maggiore Hospital, Milan, Italy e Angiology Unit, University of Bologna, Bologna, Italy f Division of Pneumology, Catholic University, Rome, Italy g Sanofi-Aventis, Milan, Italy article info abstract Article history: Received 21 November 2011 Received in revised form 5 March 2012 Accepted 9 April 2012 Available online 13 May 2012 Keywords: Venous Thromboembolism Deep Venous Thrombosis Pulmonary Embolism Long-Term Follow Up Death Recurrent VTE Background: The long-term clinical outcome of VTE has been essentially assessed in cohorts of selected patients. The aim of this multicenter registry was to prospectively assess the long-term clinical outcome in a cohort of unselected patients with objectively confirmed acute VTE. Materials and Methods: Death and VTE recurrence at 24 months were the main study outcomes. Univariate and multivariate survival analyses were performed according to the Kaplan-Meyer and Cox proportional hazard model, respectively. Results: 2119 patients with acute VTE were included in the registry: 1541 (72.7%) withdeepveinthrombosis,206 (9.7%) with pulmonary embolism and 372 (17.6%) with both. Information about death was available in 2021 patients (95.4%) and about recurrence in 1988 patients (93.8%). 167 patients (4.55% patient-year) died during follow-up. After adjusting for age, cancer (Hazard ratio [HR]: 7.2; 95%CI ), long-term heparin treatment (HR: 2.5; 95%CI ), in-hospital management of VTE (HR: 2.0; 95%CI ), and ileo-caval thrombosis (HR: 1.7; 95%CI ) were found to be independent predictors of death. 124 (3.63% patient-year) patients had a VTE recurrence during follow-up. In-hospital management of VTE (HR: 1.8; 95%CI ), male gender (HR: 1.7; 95%CI ) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI ) showed a trend for increased risk of VTE recurrence (p=0.056). The reported rate of major bleeding was 2.5%. Conclusions: In a large cohort of unselected VTE patients, cancer, ileo-caval thrombosis, long-term heparin treatment and in-hospital management were associated with increased mortality during long-term follow-up. In-hospital management, male gender were associated with an increased risk of VTE recurrence Elsevier Ltd. All rights reserved. Introduction Long term outcome studies in patients with venous thromboembolism (VTE) are often retrospective, have a reduced sample size, and tend to include selected populations. In addition, some of these studies were performed several years ago, often in a single center [1 3] or were based on administrative data rather than on direct patient observation Abbreviations: VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism. MASTER investigators and study centers are listed on page 15. Corresponding author at: Sezione di Medicina Interna e Cardiovascolare Stroke Unit, Dipartimento di Medicina Interna, Università di Perugia, Via Gerardo Dottori, 06100, Perugia, Italy. Tel.: ; fax: address: melina.verso@unipg.it (M. Verso). [4]. Two comprehensive VTE registries provide extensive information after a relatively short-term follow up [5,6]. Relatively few contemporary data on long-term clinical outcomes are available from prospective cohorts of VTE unselected patients. MASTER is a prospective, multicenter registry specifically designed to collect data about long-term clinical outcomes in unselected patients with an acute symptomatic, objectively confirmed pulmonary embolism (PE) and deep vein thrombosis (DVT). The observation period was 24 months. Death and recurrence of VTE were the main study outcomes. Design and Methods The objective of the MASTER registry was to obtain clinical information on long-term clinical outcomes in a large cohort of unselected patients with VTE /$ see front matter 2012 Elsevier Ltd. All rights reserved. doi: /j.thromres

2 370 M. Verso et al. / Thrombosis Research 130 (2012) Patients We included consecutive patients, aged 18 years or older, with an acute symptomatic, objectively confirmed VTE (deep vein thrombosis, pulmonary embolism or both), who survived after the acute phase of disease and had a life-expectancy of at least 3 months. The study was performed in 25 Italian centers. The study design and the inclusion and exclusion criteria were previously reported in details [7]. The registry did not issue diagnosis algorithms or guidelines for patient management. The follow up period started at the time of first VTE. Data Collection Clinical information were captured through an electronic data network, at the time of the index event and at follow-up visits scheduled for up to 24 months. Demographic characteristics, clinical presentation, risk factors for VTE, diagnostic work-up and treatment were collected as reported elsewhere as well as were the methods of electronic data capture, guarantees for patient's privacy and quality of entered data [7]. After inclusion in the MASTER registry, all patients were seen in the out-patient clinic 6, 12 and 24 months after the index event. In addition, telephone contacts were scheduled at 3, 9, 15, 18 and 21 months. During the long-term follow up, information were collected about the following outcomes: death, recurrent VTE (DVT, PE or both), major bleeding, newly diagnosed cancer, stroke, acute myocardial infarction and post-thrombotic syndrome. No central adjudication of index and emergent VTE events was performed. Information about antithrombotic treatment and treatmentassociated bleedings were also recorded. Major and minor bleedings were defined following the ISTH criteria [8]. The study protocol did not dictate any recommendation about patient management. The choice of diagnostic methods and treatment of the VTE event were left to the attending physicians in the participating centers. Data Analysis The Incidence Rates (IR) for death or recurrence of VTE were estimated according to the Kaplan-Meier method. The Log Rank test was used to estimate the significance of differences between IR. The Hazard Rates (HR) for death or recurrence of VTE were estimated according to the Cox proportional hazard model. Independent variables were included in the model according to the plausibility of their relevance as determinant, confounder, or effect modifier. A stepwise Cox PH model is used with the P Value for a characteristic entering of b0.10 and for a characteristic leaving of >0.20. The Risk Ratios of the cumulative incidence of bleeding, postthrombotic syndrome or arterial thrombosis during the follow up period were analyzed according to the logistic regression model. Only variables measured at the time of recruitment were introduced in the models as fixed determinants of each outcome. All analyses were performed using the EPI-INFO package (Center for Disease Control, Atlanta, USA 2005) and STATA 10 packages. For patients providing information on clinical follow up beyond 24 months, the maximum period considered for the analyses was truncated at 810 days. The study results were confirmed at a sensivity analysis performed in 1836 patients with no less than 610 days of follow up. Results Baseline Patient Characteristics A total of 2119 consecutive patients were included in the registry. The description of demographic characteristics, clinical presentation, risk factors for VTE, diagnostic work-up and treatment of the index event were previously reported in details [7] and summarized in Table 1. The major epidemiological features of the overall study MASTER cohort did not differ from those of patients included in the analyses of death and recurrence (Table 2). Long-term Death and its Major Determinants Information about death at 24 month-follow up were available in 2021 patients (95.4%): 1002 males and 1019 females. 167 (4.55%p-y) patients died (Fig. 1). Mortality was 1.43%p-y in patients with unprovoked VTE, 20.32%p-y in patients with cancer and 1.73%p-y patients with VTE associated with temporary risk factors (Log-Rank test=362.7, pb0.001). Co-variates included in the analysis and relative HRs are shown in Table 3. Independent predictors of death were cancer (HR: 7.2; 95%CI ), long-term heparin treatment (HR: 2.5; 95%CI ), inhospital management of VTE (HR: 2.0; 95%CI ), and ileo-caval thrombosis (HR: 1.7; 95%CI ). Elastic stockings were associated with reduced mortality (HR: 0.6; 95%CI ). No significant difference in mortality rate between PE and DVT patients was observed. Recurrence of Venous Thromboembolic Events and its Major Determinants Information about recurrence of VTE were available in 1988 patients (93.8%): 983 males and 1005 females. 124 (3.63%p-y) patients presented at least one VTE recurrence (Fig. 2). 101 patients (81.5%) recurred with DVT and 23 patients (18.5%) with PE. The rate of recurrence was 4.50%p-y in patients with unprovoked VTE, 4.80%p-y in patients with cancer and 2.06%p-y in patients with VTE associated with temporary risk factors (Log-Rank test=14.60, pb0.001). The recurrence rates were 3.84%p-y in patient with DVT alone and 3.09%p-y (Log-Rank test=1.05, n.s.) in those with PE (with or without DVT). Patients with PE as the index event presented VTE recurrence as PE in 2.7% and as DVT in 2.7% of cases. Patients with DVT as the index event presented VTE recurrence as PE in 0.6% and as DVT in 6.0% of cases. The type of the index event was a strong predictor of the type of recurrence (OR 10.7; 95% CI ). Co-variates included in the Cox model analysis and relative HR are shown in Table 4. In-hospital management of VTE (HR: 1.8; 95%CI 1.2- Table 1 Description of the study cohort. Main characteristics of the overall population N (%) N (%) Mean age 59.3± Patients with known cancer 381 (18) 18.1 yr Male gender 1056 (49.8) Patients with new diagnosed 50 (2.3) cancer Clinical features of 1789 (94.2) Temporary risk factors ( 1) 899 (42.4) lower limb DVT Left 1013 (56.6) right 776 (43.4) Surgery 306 (14.4) bilateral 114 (5.9) Immobility (b7 days) 318 (15.0) proximal 1147 (64.2) Severe medical disease 174 (8.2) distal 642 (35.8) Pregnancy 30 (1.4) inferior caval vein 50 (2.6) Post-partum 37 (1.7) involvement Clinical features of 124 (5.8) Oral contraceptives 114 (5.4) upper limb DVT Left 62 (50) CVC 5 (0.5) Right 62 (50) Trauma and fractures 202 (9.5) Bilateral 0 Other 83 (3.9) Superior caval vein involvement 7 (0.4) *proximal: DVT with involvement of iliac- femoral and/or popliteal veins; distal: without popliteal vein involvement. ** Upper limb DVT were all proximal involving the axillo-subclavian segment.

3 M. Verso et al. / Thrombosis Research 130 (2012) Table 2 Description of overall study cohort and of cohorts divided according to major outcomes. 2.9), male gender (HR: 1.7; 95%CI ) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI ) showed a trend for increased risk of VTE recurrence (p=0.056). The presence of temporary risk factors was associated with a significant reduction in the recurrent rate of VTE event (HR: 0.4; 95%CI ). No significant difference in the recurrent rate of VTE was observed between patients whit lower-limb DVT or patients with upper limb DVT. The death rate of patients with recurrent VTE was 16.5%p-y in comparison with 4.20&p-y of patients without recurrent VTE (Log-rank test=8.97, pb0.001). Major Bleeding Overall population Mortality population VTE recurrence pop. N=2119 N=2021 N=1988 n % n % n % VTE managment In-hospital patients Out-patients Male gender ,4 Age classes 40 yrs yrs yrs yrs Type of VTE events Isolated DVT Isolated pulmonary embolism Pulmonary embolism and DVT ,6 Risk factors for VTE Known cancer Known thrombophilia Previous VTE Temporary (one or more) Information about bleeding, post-thrombotic syndrome, incident cancer, and arterial thrombosis was available in 1883 patients with at least one complete follow-up visit. The incidence of major bleeding was 2.5% (48/1883): 5.5% (20/363) in patients with cancer either known at the time of the study inclusion or diagnosed during the study period and Table 3 Multivariate analysis of predictors of death. Covariates Hazard Ratio 95%CI* P value Male Age b In-hospital management of VTE Thrombolysis Previous VTE Cancer b Temporary risk factors Chemotherapy Prescription of elastic stockings Long-term treatment with heparin b Pulmonary embolism No anticoagulation Caval filter Ileo-caval DVT % (28/1520) in patients without cancer, corresponding to an OR of 3.1 (95%CI ). No fatal bleeding was reported. Bleeding occurred in 1.7% and 2.7% (OR: 0.6; 95%CI ) of patients while they were receiving heparin or vitamin K antagonists, respectively. In-hospital management of VTE (OR: 3.6; 95%CI ), and cancer (OR: 3.2; 95%CI ) were independent risk factors for bleeding complications. Post-thrombotic Syndrome The cumulative incidence of post-thrombotic syndrome was 9.7% (182/1883). The incidence was higher in patients with known cancer (92/363, 25.3%) than in patients without known cancer (90/1520, 5.9%) corresponding to an OR of 5.4 (95%CI ). The independent risk factors for post-thrombotic syndrome were: in-hospital management (OR: 2.5; 95%CI ), and cancer (OR: 5.7; 95%CI ) while the presence of temporary risk factors (OR: 0.7; 95%CI ), and prescription of elastic stocking (OR: 0.8; 95%CI ), were found as borderline significant protective factors for post-thrombotic syndrome. Newly Diagnosed Cancer The cumulative incidence of newly diagnosed cancer during 24-months follow up was 1.3% (25/1883). The type of cancer was: gastrointestinal cancer in 7 patients, genitourinary cancer in 5 patients, hematologic cancer in 4 patients, lung cancer in 3 patients, central nervous system cancer in 3 patients, breast cancer in 1 patient and other cancer types in 2 patients. Fig. 1. Survival in the study population. Fig. 2. VTE recurrence according to gender distribution.

4 372 M. Verso et al. / Thrombosis Research 130 (2012) Table 4 Multivariate analysis of predictors of VTE recurrence. Covariates Hazard Ratio 95%CI P value Male Age In-hospital management of VTE Thrombolysis Previous VTE Cancer Temporary risk factors b Chemotherapy Prescription of elastic stockings Long-term treatment with heparin No anticoagulation Caval filter Pulmonary embolism Ileo-caval DVT Proximal DVT Upper limb DVT confidence intervals. Arterial Thrombosis The cumulative incidence of arterial thrombotic complications was 1.1% (20/1883): 0.7% (14/1883) acute myocardial infarction and 0.4% (8/1883) ischemic stroke. Cancer was an independent risk factor for acute myocardial infarction (OR: 3.5; 95%CI ) and a previous VTE was an independent risk factor for any acute arterial thrombosis occurrence (OR: 2.8; 95%CI ). No cases of arterial thrombosis of the legs were observed. Discussion This prospective, follow-up registry of consecutive patients with objectively confirmed VTE showed a mortality rate of 4.55% patientyear. This rate confirms that patients with VTE have a mortality rate that is 4 times higher than that of a population without VTE [2]. As expected, the mortality rate was highest in patients with cancer, while there was no significant difference between patients with unprovoked and provoked VTE. Previous data suggest that survival rates after PE are lower than after DVT alone [1]. Our study found no difference in terms of long-term mortality between these two groups. The fact that PE was not a predictor of survival (in comparison with DVT alone) might be explained with the exclusion of the rapid deaths due to massive PE from the Registry. We observed a drop in survival occurring at 180 days. We believe that this observation could be explained with the high rate of cancer patients who died for the progression of disease. In addition to cancer, ileo-caval thrombosis, in-hospital management of VTE and long-term heparin treatment were independent predictors of death. Noteworthy, the prescription of elastic stockings in patients with lower limb DVT was associated with reduced mortality. The possible explanation of this observation may be that VTE patients who receive prescription of elastic stockings have a lower number of co-morbidities (as peripheral arterial disease or diabetes) and have thus a better prognosis. In addition, about 70% of the included patients were managed as in-patients. The observation that in-hospital management was found as independent risk factor for death may reflect the worsen clinical condition of patients admitted in hospital in comparison with patients managed as out-patients. The VTE recurrence rate observed in this registry was 3.63% patient-year. We confirmed and reinforced the evidence that patients with VTE can be stratified in order to individual risk into high and low risk of VTE recurrence according to persistent or transient baseline patients characteristics. For example, as expected, the VTE recurrence rate was higher in patients with unprovoked VTE and in cancer patients. The rate of VTE recurrence in cancer patients was lower than the rate reported in previous studies. In 355 cancer patients with DVT, Prandoni et al [9] reported a 2-years cumulative incidence for VTE recurrence of 17.5%. The rate of VTE recurrence in our registry was closer to that reported in the LMWH group in an interventional study in cancer patients [10]. We confirmed that male gender is an independent risk factor for recurrent VTE [11 13]. In contrast with data reported by Kyrle et al [11], we observed this significant difference in recurrence rate particularly in patients with clinically relevant VTE events, such as proximal DVT and/or PE. Our findings did not show a significant difference in the risk of VTE recurrence in relation to the type of VTE. In particular, an incident PE was not associated with a greater risk of recurrence than DVT of the lower limbs or the upper limbs. Nearly all patients received long-term oral anticoagulation or LMWH treatment at least of 6 months. The observed rate of major bleeding was 2.5%, most of them related to anticoagulant treatment. The rates of major bleeding in previous cohort study [14] was higher than that reported in our registry. No fatal event was documented. Our findings on safety of anticoagulant treatment were more similarly to data derived from recent randomized trial on VTE management than that reported in other registries [4 6,15]. In the Worcester study [14] the rate of major bleeding was about 11% and 14% at 1 year- and at 3 year-follow up, respectively. In addition, similar to findings from the Worcester study, the rate of major bleeding was similar between patients with PE and patients with isolated DVT. We confirmed previously reported data concerning the higher risk of major bleeding in patients with cancer rather than patients without cancer [16]. The clinically relevant symptoms of post-thrombotic syndrome were reported in about 10% of overall population. The reported rates at 6 months of post-thrombotic syndrome in a previously published study [17] were about 35% for any class and 10% for moderate-severe post-thrombotic syndrome. The rate of arterial complications (IMA and ischemic stroke) was lower in comparison with venous recurrence in this population. No suggestions can be made in relation to the strength of this clinical association. Our registry has several potential limitations, including the absence of the central adjudication of the recurrent VTE events, the absence of standardized duration of long-term treatment, the lack of screening of inherited thrombophilia at the time of the index event and the lack of collection of cancer information about cancer histology and staging, as well as type and duration of chemotherapy regimens in cancer patients. In addition, in order to focus the primary objective of this registry on the long term follow up, it was predefined that patients with a life expectancy of less than 3 months or not able to perform scheduled follow up visits were excluded. This choice could have had an effect on the evaluation of mortality rate. However, the strength of this study was the high rate of included patients with 24-months follow-up, that was about 95% for death and VTE recurrence. Recent contemporary registries of patients with VTE are able to provide information on short-term follow up period [4 6,18]. MASTER is a registry on consecutive patients with VTE, designed to assess demography, risk factors, management and the long-term clinical outcome of the disease in an unselected population. Given its structure and design, MASTER is likely to provide information that is more generalizable than that achieved from interventional studies carried out in selected populations. The Italian MASTER Registry was supported by an unrestricted educational grant from Sanofi-Aventis; the pharmaceutical company had no role in analyzing the data or preparing the manuscript. Conflict of Interest Statement W. Ageno, G. Agnelli, D. Imberti, M. Moia, G. Palareti, R. Pistelli and M. Verso received fees from Sanofi-Aventis.

5 M. Verso et al. / Thrombosis Research 130 (2012) Appendix I. Participating Investigators and Study Sites Study coordinating Center: G. Agnelli, M. Verso, Division of Internal and Cardiovascular Medicine- Stroke Unit, University of Perugia, Perugia, Investigators: W. Ageno: Ospedale di Circolo Macchi,Varese, M. Bellisi: Policlinico Paolo Giaccone, Palermo, M. Bianchi: Ospedale Valduce, Como, V. Brancaccio: Azienda Ospedaliera Cardarelli, Napoli, A. Ciampa: Azienda Ospedaliera S. G. Moscati, Avellino, C. Cimminiello: Ospedale Civile di Vimercate, Vimercate, Milan, A. Dragani: Ospedale Civile dello Spirito Santo, Pescara, S. Grifoni: Azienda Ospedaliera Careggi, Firenze, D. Imberti: Ospedale Civile di Piacenza, Piacenza, A. M. Impagliatelli: IRCCS Casa del Sollievo e della Sofferenza, S.Giovanni Rotondo, Foggia, G. Iovane: ASL Bianchi Melacrino-Morelli, Reggio Calabria, R. Margheriti: Ospedale G. B. Grassi, Roma, M. Moia: Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena di Milano, Milan, S. Musumeci: Ospedale Vittorio Emanuele II, Catania, G. Palareti: Policlinico S Orsola- Malpighi,Bologna, M. Pini: Ospedale Civile di Fidenza, Fidenza, Parma, P.A. Pittaluga: Ospedale di Galliera, Genoa, V. Prisco: ASL SA/2, Mercato San Severino, Salerno, S. Rupoli: Ospedale regionale Torrette, Torrette di Ancona, Ancona, G. Scannapieco: Ospedale Civile Ca Foncello, Treviso, S. Signorelli: Ospedale Garibaldi, Catania, M. Silingardi: Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, S. Siragusa: Policlinico Paolo Giaccone, Palermo, V. Virgilio: Ospedale Garibaldi, Catania, Catania, Italy. References [1] Heit J, Silverstein M, Petterson T, O'Fallon W, Melton L. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999;159: [2] Heit J, Mohr D, Silverstein M, Petterson T, O'Fallon W, Melton L. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 2000;160: [3] Prandoni P, Lensing A, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep vein thrombosis. Ann Intern Med 1996;125:1 7. [4] Spencer FA, Gore JM, Lessard D, Douketis JD, Emery C, Goldberg RJ. Patient Outcomes After Deep Vein Thrombosis and Pulmonary Embolism The Worcester Venous Thromboembolism Study. Arch Intern Med 2008;168: [5] Arcelus JI, Caprini JA, Monreal M, Suarez C, Gonzalez-Fajardo J. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg 2003;38: [6] Goldhaber SZ, Tapson VF. for the DVT FREE steering Committee. A prospective registry of patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 2004;93: [7] Agnelli G, Verso M, Ageno W, Imberti D, Moia M, Palareti G, et al. 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