ALBERT

Description: Abstract 544 Background. In patients with unprovoked venous thromboembolism (VTE) occurring in the absence of major provoking factors, the optimal duration of anticoagulation is anchored on estimating the risk for disease recurrence in the individual patient. Evidence from several studies suggests that, at least in selected patient subgroups, the risk for recurrence may approximates the annual risk for anticoagulant-related major hemorrhage, which is estimated at 1–3%, and a recent ISTH consensus considers an annual risk of recurrence below 5% as acceptable to justify stopping anticoagulant therapy. Aim. To develop a clinical prediction guide that stratifies patients according to recurrence risk and, thereby, facilitate decisions about whether to continue or stop anticoagulation. Methods. Individual patient data meta-analysis of 7 prospective studies enrolling patients with a first episode of objectively diagnosed VTE. Eligible VTE cases were those which occurred in the absence of surgery, trauma, active cancer, immobility, or pregnancy and the puerperium. Follow-up started when anticoagulant therapy was stopped and ended when one of the following occurred: symptomatic, objectively documented, recurrent VTE; death from another cause; resumption of anticoagulant therapy for another reason; or the study ended. Predictors were identified using stratified Cox regression, and the weight of predictors was obtained after model shrinkage to correct for over-optimism. The discriminative ability of the prediction rule was estimated using time-dependent c-statistics, and was internally validated by bootstrap analysis. Results. 1818 consecutively referred cases with unprovoked VTE treated for at least three months with a vitamin K antagonist were eligible for analysis. Abnormal D-dimer after stopping anticoagulation, age 〈 50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence. Optimism-corrected regression coefficients were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy), that showed a good predicting capability (ROC area=0.71). The DASH score attributes the following points: +2 for positive (abnormal) post-anticoagulation D-dimer, +1 for age ≤ 50 years, +1 for male sex, −2 for hormone use at time of initial VTE (in women only). The annualized recurrence risk was 3.1% (95% confidence interval [CI] 2.3 – 3.9) in patients with a DASH score ≤ 1, 6.4% (95% CI 4.8–7.9) in patients with a DASH score 2, and 12.3% (95% CI, 9.9–14.7) in patients with a DASH score ≥ 3, as reported by the Kaplan-Meier recurrence-free survival plot. By considering at low recurrence risk those patients with a DASH score ≤ 1, life-long anticoagulation might be avoided in 51.6% of patients with unprovoked VTE. Conclusions. The DASH score appears to reliably predict recurrence risk in patients with a first unprovoked VTE and may be used to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at last three months. Patients with a DASH score ≤ 1 appear to have an annual risk for recurrence (3.1%) that may be sufficiently low to justify stopping anticoagulation in an average patient after 3–6 months of anticoagulation, whereas a DASH score ≥ 2 appears to confer a risk of recurrent VTE that may warrant indefinite anticoagulation. Disclosures: No relevant conflicts of interest to declare.

Description: Thromboses limited to infrapopliteal leg deep veins (isolated distal deep vein thrombosis [IDDVT]) are frequently diagnosed in subjects with suspected pulmonary embolism or DVT and account for one-fourth to one-half of all diagnosed leg DVTs. Despite their frequency, the natural history of IDDVTs and their real risk of thromboembolic complications are still uncertain because of the scarcity of prospective, blind, nonintervention studies. Therefore it is still debated whether they warrant diagnosis and treatment. Diagnosis is based on ultrasonographic examination, which is more operator dependent and less sensitive in distal than in proximal veins. The available data seem to support the view that most IDDVTs are self-limiting and inconsequential for patients, though in some cases they can be associated with complications and warrant diagnosis and treatment. The available guidelines for treatment of IDDVTs give different indications ranging from serial imaging of the deep veins for 2 weeks to detect and treat only in case of proximal extension, to giving oral anticoagulation in all IDDVT patients for 3 months. I review this issue, focusing on possible and suggested treatments in symptomatic IDDVT patients, and describe our current therapeutic approach to these patients.

Description: Key Points The duration of anticoagulation after VTE is uncertain; this management study intended to identify patients with low/high recurrence risk. Patients with persistently negative D-dimers after stopping standard therapy have a low recurrence risk and can stop anticoagulation.

Description: Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) is uncertain. Anticoagulant therapy is highly effective at reducing the risk of recurrent VTE, but this clinical benefit is not maintained once anticoagulation is stopped. Current guidelines suggest considering indefinite anticoagulation in all patients with unprovoked who have a non-high bleeding risk. However, this is a weak recommendation based on limited evidence. Deciding whether patients with a first unprovoked VTE should be considered for indefinite anticoagulant therapy requires estimation of the long-term risk of recurrent VTE after stopping anticoagulation. This risk however, is poorly established, hindering decision making. Methods: We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to determine the rate of recurrent VTE in the first year, in the second year, between years 2 and 5, and years 5 and 10; and the cumulative incidence for recurrent VTE at 2, 5 and 10 years after stopping anticoagulation in men and women with first unprovoked VTE, who had completed at least 3 months of initial treatment. Studies were identified through a comprehensive literature search using MEDLINE, EMBASE and the Cochrane CENTRAL databases. Data clarifications were requested from authors of eligible studies. Rates of recurrent VTE were calculated for each study from the total number of recurrent VTE events divided by the person-years of follow-up, and then pooled using random-effects meta-analysis. Results: Fourteen studies involving 6, 446 patients were included in the analysis. Among men with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 11.2 events (95% CI, 9.0-13.6) in the first year; 7.4 events (95% CI, 5.5-9.5) in the second year; 4.4 events/year (95% CI, 3.2-5.7) between years 2 and 5, and 3.8 events/year (95% CI, 1.6-6.9) between years 5 and 10 [Table 1]. Among women with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 8.6 events (95% CI, 6.5-11.0) within the first year; 5.2 events (95% CI, 3.5-7.2) in the second year; 3.0 events/year (95% CI, 1.6-4.7) between years 2 and 5, and 2.0 events/year (95% CI, 1.3-2.9) between years 5 and 10 [Table 1]. In men and women respectively, the cumulative incidence for recurrent VTE was 17.8% (95% CI, 14.0%-21.9%) and 13.4% (95% CI, 9.8%-17.4%) at 2 years, 28.2% (95% CI, 22.0%-34.4%) and 20.9% (95% CI, 14.0%-28.5%) at 5 years, and 40.8% (95% CI, 28.0%-53.9%) and 28.5% (95% CI, 19.5%-38.3%) at 10 years after stopping anticoagulant therapy [Table 2]. Conclusions: Among patients with a first unprovoked VTE who have completed at least 3 months of initial treatment, men have a higher long-term risk of recurrent VTE after stopping anticoagulation, and may be given greater consideration for indefinite anticoagulant therapy. Our findings affirm the importance of considering patient's sex in deciding the optimal duration of anticoagulation, and as such, emphasize the need for individualized, patient-centered approach for the long-term management of unprovoked VTE. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Research Funding; Pfizer: Honoraria; Bayer: Honoraria. Weitz:Bristol-Myers Squibb: Honoraria; Daiichi-Sankyo: Honoraria; Ionis: Consultancy, Honoraria; Janssen: Honoraria; Servier: Honoraria; Novartis: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria. Couturaud:Pfizer: Research Funding; Bayer: Honoraria, Other: Travel Support; AstraZeneca: Honoraria; Actelion: Other: Travel Support; Intermune: Other: Travel Support; Leo Pharma: Other: Travel Support; Daiichi Sankyo: Other: Travel Support. Becattini:Bayer HealthCare: Other: Lecture Fees; Boehringer Ingelheim: Other: Lecture Fees; Bristol Meyer Squibb: Other: Lecture Fees. Agnelli:Daiichi Sankyo: Other: Personal Fees; Boehringer Ingelheim: Other: Personal Fees; Bayer Healthcare: Other: Personal Fees; Pfizer: Other: Personal Fees; Bristol-Myers-Squibb: Other: Personal Fees. Brighton:Glaxo Smith Klein: Other: Personal Fees; Novo Nordisk: Other: Personal Fees; Bayer: Other: Personal Fees. Lensing:Bayer: Employment. Prins:Pfizer: Consultancy; Daiichi Sankyo: Consultancy. Hutton:Cornerstone Research Group: Honoraria. Palareti:Roche: Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Alfa-Wassermann: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Prandoni:Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Büller:Pfizer: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding; Isis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Rodger:Biomerieux: Research Funding.

Description: Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

Description: Background: Venous thromboembolism (VTE) has a tendency to recur after anticoagulation is stopped. The optimal duration of anticoagulation is influenced by the risk of recurrence: indefinite anticoagulation is recommended after a first VTE associated with a persistent and strong risk factor (e.g. cancer), whereas three months of anticoagulation is adequate if VTE was provoked by a transient risk factor (e.g. surgery). The optimal duration of anticoagulation after a first unprovoked VTE is, however, still a matter of debate. An attractive approach is to identify subgroups of patients with unprovoked VTE who have a high risk of recurrence and treat them with prolonged anticoagulation, and subgroups with a lower risk of recurrence and treat them for only three months. A critical issue, therefore, is to determine a cut-off value for risk of recurrence that is low enough to justify stopping anticoagulant therapy at three months (i.e., a rate of recurrence that is acceptable to patients and physicians). We propose that the rate of recurrence after VTE that was provoked by a transient risk factor represents such a value. Aim of the study: To accurately estimate the risk of recurrence in patients with VTE provoked by a transient risk factor who have completed at least three months of anticoagulant therapy. Materials and Methods: Medline, Embase and Cochrane Collaboration Registry of Randomized Trials were searched for any studies reporting the recurrence rate of VTE after a first episode of VTE associated with a transient risk factor (surgery, trauma, plaster, bed rest, pregnancy, puerperium, hormone treatment). The references of retrieved articles were scanned for any additional relevant studies. Studies were included if enrolling patients met the following criteria: a first episode of VTE provoked by a transient risk factor; a course of at least three months of oral anticoagulant therapy; a follow up of 12 or 24 months after treatment discontinuation with assessment of VTE recurrence rate. Recurrence rate, or data that allowed its calculation, needed to be reported. An overall estimate of the recurrence rate was calculated following Laird (Stats Med 1990), having predefined to use a fixed-effect model if no heterogeneity was found among the studies or a random-effect model otherwise. The inverse variance method was used to calculate weights for the studies. Results: The literature search yield 1089 references. After careful scanning of the potentially relevant papers, 15 papers were included in the final analysis. All studies except one were prospective. 12/15 and 11/15 studies reported data about the recurrence rate at 12 and 24 months, respectively. Overall there were 106 events among of 2217 patients at 12 months and 160 events among 2321 patients at 24 months. The pooled recurrence rate was 4.0% (95% C.I. 3.0%–5.2%) at 12 months and 6.7% (95% C.I. 5.2%–8.6%) at 24 months. Conclusion: The cumulative risk of recurrence in patients with VTE provoked by a reversible risk factor is 6.7% (95% C.I. 5.2%–8.6%) two years after anticoagulant withdrawal. We suggest that it acceptable to stop anticoagulant therapy after three months in subgroups of patients with unprovoked VTE who have been shown to have a risk of recurrence that is similar to, or lower than, this rate.

Description: The PROLONG randomized trial showed that a normal D-dimer (D-d) 1 month after anticoagulation suspension for unprovoked venous thromboembolism (VTE) was associated with a low risk of late recurrences (4.4% patient years). However, it is unknown whether D-d changes subsequently. The aim of this prospective multicenter study was to assess D-d time course and its relation with late recurrences in patients with normal D-d 1 month after anticoagulation suspension for a first episode of unprovoked VTE. D-d was measured with a qualitative method (Clearview Simplify D-dimer; Inverness Medical Professional Diagnostics). Patients with a normal D-d 1 month after stopping anticoagulation repeated D-d testing every 2 months for 1 year. D-d was normal in 68% (243/355) of patients 1 month after anticoagulation suspension. Patients in whom D-d became abnormal at the third month and remained abnormal afterward had a higher risk of recurrence (7/31; 27% patient years; 95% confidence interval [CI]: 12-48) than patients in whom D-d remained normal at the third month and afterward (4/149; 2.9% patient years; 95% CI: 1-7; adjusted hazard ratio: 7.9; 95% CI: 2.1-30; P = .002). Repeated D-d testing after anticoagulation suspension for a first episode of unprovoked VTE could help tailor the duration of treatment. This trial is registered at http://clinicaltrials.gov as NCT00266045.