Bleeding with Apixaban and Dalteparin in Patients with Cancer-Associated Venous Thromboembolism: Results from the Caravaggio Study.

BACKGROUND: Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding risk in patients with gastrointestinal cancer was reported. The Caravaggio study compared apixaban and dalteparin for the treatment of patients with CAT. Here we describe sites of bleeding, associated cancer sites, clinical presentation, and course of major bleeding in patients included in the Caravaggio study. METHODS: The Caravaggio study was a multinational, randomized, open-label, noninferiority study. Bleeding events and the severity of major bleedings were adjudicated by a committee unaware of treatment allocation using predefined criteria; for the purpose of this analysis, data were analyzed in the safety population. RESULTS: Major bleeding occurred in 22 of 576 patients on apixaban (3.8%) and in 23 of 579 patients on dalteparin (4.0%). The sites of major bleeding and their distribution according to the type of cancer were similar between the two treatment groups. Major bleeding occurred in nine patients with gastrointestinal cancer in each treatment group. The clinical presentation of major bleeding was severe or fatal in 6 patients on apixaban and in 5 patients on dalteparin, while the clinical course was severe in 5 patients on apixaban and in 7 patients on dalteparin. CONCLUSION: Apixaban is a safe alternative to LMWH for the treatment in patients with CAT. No excess in gastrointestinal bleeding was observed in patients who received apixaban, including those with gastrointestinal cancer.

Effect of thrombophilia on clinical outcomes of chronic post-thrombotic patients after iliofemoral stenting with nitinol venous stents.

OBJECTIVE: Thrombophilia is a prothrombotic condition that increases the risk of venous thromboembolism. It is unclear whether the presence of thrombophilia alters the clinical outcomes after deep venous stenting. The aim of the present study was to examine the relationship between thrombophilia and outcomes after stenting for post-thrombotic syndrome. METHODS: Consecutive patients (2012-2017) receiving a nitinol venous stent for chronic post-thrombotic venous occlusive disease with a minimum of 18 months of follow-up in one center using the same anticoagulation protocol were included. The clinical history and thrombophilia testing results were reviewed. The outcomes were stent patency, which was assessed using duplex ultrasonography at 24 hours, 2 and 6 weeks, 3 months, 6 months, and annually thereafter; and reinterventions, which were performed when the stent diameter was <50% or occluded. RESULTS: Of the 136 patients who had undergone intervention, 55 (40%) had had a provoked deep vein thrombosis (DVT) and 81 (60%) had had an unprovoked DVT and had therefore undergone thrombophilia testing. Of the 81 patients, 38 (47%) had had either inherited (n = 19; 50%) or acquired (n = 19; 50%) thrombophilia. Of the 136 patients who had undergone stenting, 68 had required reintervention (50%) during follow-up to maintain stent patency. Of the 55 patients with a provoked DVT, 29 (53%) had required reintervention. Of the 81 patients with an unprovoked DVT, 39 (48%) had required reintervention (P = .420). Of the 38 patients with unprovoked DVT and thrombophilia, 17 (45%) had required reintervention. Of the 43 patients with unprovoked DVT and no thrombophilia, 22 (51%) had required reintervention (P = .766). The cumulative patency rate was 80% for patients with provoked DVT and 88% for those with unprovoked DVT (P = .193). The presence of thrombophilia was not associated with patency loss (92% cumulative patency for patients with thrombophilia and 84% for patients without thrombophilia; P = .307). CONCLUSIONS: Using our anticoagulation protocol, patients with and without thrombophilia had similar clinical outcomes after deep venous stenting and should not be excluded from iliofemoral venous stenting. We found no significant differences in outcomes in conjunction with appropriate postoperative anticoagulation therapy.

AngioJet Pharmacomechanical Thrombectomy and Catheter Directed Thrombolysis vs. Catheter Directed Thrombolysis Alone for the Treatment of Iliofemoral Deep Vein Thrombosis: A Single Centre Retrospective Cohort Study.

OBJECTIVE: Percutaneous thrombus removal is used for the treatment of iliofemoral deep vein thrombosis (DVT), but the efficacy of different treatment modalities has not yet been determined. The aim of this study was to compare the outcomes of patients treated with additional AngioJet pharmacomechanical thrombectomy (PCDT) vs. catheter directed lysis (CDT) alone. METHODS: A retrospective review of all patients who received thrombolysis for the treatment of symptomatic acute iliofemoral DVT between 2011 and 2017 was carried out. Outcome measures included the incidence of post-thrombotic syndrome (PTS), procedural outcomes (lytic exposure), the incidence of complications, and vessel patency. All patients were followed up for a minimum of one year. RESULTS: A total of 151 limbs were treated, 70 limbs with PCDT and 81 limbs with CDT alone. Demographic data and prevalence of risk factors were comparable. Incidence of PTS (Villalta score at one year) showed no significant difference (22.2% PCDT vs. 24.7% CDT alone, p = .74). Use of PCDT resulted in a non-statistically significant trend for fewer bleeds (n = 4/63 [6.3%] vs. 13/76 [17.1%]; relative risk 0.37, 95% confidence interval [CI] 0.13-1.08; p = .07), a statistically significant reduction in lysis duration (40 h [95% CI 34-46] vs. 53 h [95% CI 49-58]; p < .001) and a reduction in lytic dose (49 mg [95% CI 42-55] vs. 57 mg [95% CI 52-61]; p = .011) compared with CDT. This reduction was accentuated in 24 cases primarily treated with AngioJet PowerPulse mode (27 h, 95% CI 20-34 [p < .001] and 42 mg, 95% CI 34-50 [p = .009]). Incidences of complications were comparable between groups, with one death due to an intracranial haemorrhage following CDT. Although the incidence of haemoglobinuria was increased following PCDT (12/63 [19.0%] vs. 3/76 [3.9%]; p = .006), no significant difference in acute kidney injury was observed (3/63 [4.8%] vs. 1/76 [1.3%]; p = .33). No significant difference in vessel patency over two years was observed (p = .73). CONCLUSION: The use of PCDT for the treatment of iliofemoral DVT was observed to provide comparable patient outcomes, comparable vessel patency, an acceptable safety profile, and reduced overall lytic dose.

Machine learning to predict venous thrombosis in acutely ill medical patients.

BACKGROUND: The identification of acutely ill patients at high risk for venous thromboembolism (VTE) may be determined clinically or by use of integer-based scoring systems. These scores demonstrated modest performance in external data sets. OBJECTIVES: To evaluate the performance of machine learning models compared to the IMPROVE score. METHODS: The APEX trial randomized 7513 acutely medically ill patients to extended duration betrixaban vs. enoxaparin. Including 68 variables, a super learner model (ML) was built to predict VTE by combining estimates from 5 families of candidate models. A "reduced" model (rML) was also developed using 16 variables that were thought, a priori, to be associated with VTE. The IMPROVE score was calculated for each patient. Model performance was assessed by discrimination and calibration to predict a composite VTE end point. The frequency of predicted risks of VTE were plotted and divided into tertiles. VTE risks were compared across tertiles. RESULTS: The ML and rML algorithms outperformed the IMPROVE score in predicting VTE (c-statistic: 0.69, 0.68 and 0.59, respectively). The Hosmer-Lemeshow goodness-of-fit P-value was 0.06 for ML, 0.44 for rML, and <0.001 for the IMPROVE score. The observed event rate in the lowest tertile was 2.5%, 4.8% in tertile 2, and 11.4% in the highest tertile. Patients in the highest tertile of VTE risk had a 5-fold increase in odds of VTE compared to the lowest tertile. CONCLUSION: The super learner algorithms improved discrimination and calibration compared to the IMPROVE score for predicting VTE in acute medically ill patients.

Two Year Outcome After Chronic Iliac Vein Occlusion Recanalisation Using the Vici Venous Stent®.

OBJECTIVE/BACKGROUND: The aim was to assess two year outcomes with placement of the Vici Venous Stent® in patients with chronic iliofemoral venous occlusions (complete blockage). METHODS: This was a retrospective single centre study comprising patients treated with the Vici Venous Stent for venographically verified iliofemoral venous occlusion and post-thrombotic syndrome (Villalta score ≥ 5 points) at least 12 months after acute deep vein thrombosis. Venography and intravascular ultrasound were used peri-operatively; duplex ultrasound was used to assess stent patency during follow up. RESULTS: Eighty-eight patients (101 limbs) had stent placement between March 2014 and October 2016. Median pre-treatment Villalta score was 14 (range 5-33). Stenting extended across the inguinal ligament in 63 limbs (62%) in order to land in a healthy venous segment. Six patients (7%) required endophlebectomy and fistula creation. Median imaging follow up was 21 months (range 0-41 months). Primary, assisted primary and secondary patency rates at one year were 59%, 78%, and 87%, respectively, and two years 51%, 73%, and 82%, respectively. Forty-three limbs (43%) had re-intervention (lysis, venoplasty, and/or placement of stent) during follow up; median time to re-intervention was 32 days (range 0-520 days). At 24 months, 37 of 53 limbs (70%) with available Villalta assessment showed clinically significant improvement (>30% reduction of baseline score). Villalta scores at the 6, 12, and 24 month clinical follow up were significantly lower than before stenting (p < .001, all time points). In a subset analyses of limbs with stenting terminating above and below the inguinal ligament, secondary cumulative patency rates at 24 months were 90% and 79%, respectively; clinical outcome showed 58% vs. 73% of limbs with clinically significant improvement, respectively. There was no statistically significant difference in patency or clinical outcomes. CONCLUSION: The Vici Venous Stent is associated with a good secondary patency rate and durable and substantial symptomatic resolution in patients with chronic post-thrombotic occlusions, regardless of whether stents extended beneath the inguinal ligament.

A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT).

BACKGROUND: Venous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study. OBJECTIVES: (1) To identify the most clinically and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT); (2) to identify practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement; and (3) to explore the barriers for progressing to a full RCT. DESIGN: The Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT) trial is a randomised, multicentre, feasibility mixed-methods study with three components: (1) a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months' treatment (current licensed practice) in patients with locally advanced or metastatic cancer, consulted in three clinical settings (haematology outpatients, oncology outpatients and primary care); (2) a nested qualitative study, including focus groups with clinicians to investigate attitudes for recruiting to the study and identify the challenges of progressing to a full RCT, and semistructured interviews with patients and relatives to explore their attitudes towards participating in the study, and potential barriers and concerns to participation; and (3) a UK-wide survey exercise to develop a classification and enumeration system for the CAT models and pathways of care. SETTING: A haematology outpatients department, an oncology outpatients department and primary care. PARTICIPANTS: Patients with ongoing active or metastatic cancer who have received 6 months of LMWH for CAT. INTERVENTIONS: Ongoing LMWH treatment for CAT versus cessation of LMWH at 6 months' treatment in patients with locally advanced or metastatic cancer. MAIN OUTCOME MEASURES: (i) The number of eligible patients over 12 months; (ii) the number of recruited patients over 12 months (target recruitment rate of 30% of eligible patients); and (iii) the proportion of randomised participants with recurrent venous thromboembolisms (VTEs) during follow-up. RESULTS: Following several delays in setting up the RCT component of the study, 5 out of 32 eligible patients consented to be randomised to the RCT suggesting progression to a full RCT was not feasible. Reasons for non-consenting were primarily based on a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Views were largely influenced by patients' initial experience of CAT. Focus groups with clinicians revealed that they would be reticent to recruit to such a study as they had fixed views of best management despite the lack of evidence. Patient pathway modelling suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination, with no consensus on which specialty should best manage such cases. CONCLUSIONS: The results of the RCT reflect recruitment from the oncology site only and provide no recruitment data from haematology centres. However, it is unlikely that these other sites would have access to more eligible patients. The management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. As it is unlikely that a prospective study will successfully recruit, other strategies to accrue relevant data are necessary. Currently the LONGHEVA (Long-term treatment for cancer patients with deep-venous thrombosis or pulmonary embolism) registry is in development to prospectively evaluate this important and common clinical scenario. STUDY REGISTRATION: This study is registered as clinical trials.gov number NCT01817257 and International Standard Randomised Controlled Trial Number (ISRCTN) 37913976. FUNDING DETAILS: Funding for the ALICAT trial was provided by the Health Technology Assessment programme (10/145/01) in response to a themed funding call. The study was designed in accordance with the initial funding brief and feedback from the review process.

D-Dimer elevation and adverse outcomes.

D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

Idraparinux versus standard therapy for venous thromboembolic disease.

BACKGROUND: Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. We investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. METHODS: We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). RESULTS: In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. CONCLUSIONS: In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 [ClinicalTrials.gov] and NCT00062803 [ClinicalTrials.gov].).

Extended prophylaxis of venous thromboembolism with idraparinux.

BACKGROUND: The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk-benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. METHODS: We randomly assigned patients who had completed 6 months of prophylaxis with idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. RESULTS: Of 1215 patients, 6 of 594 (1.0%) in the idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P=0.002). Major bleeding occurred in 11 patients (1.9%) in the idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). CONCLUSIONS: During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279 [ClinicalTrials.gov].).

Thromboembolic disease in surgery for malignancy-rationale for prolonged thromboprophylaxis.

Patients undergoing surgery for malignancy are at increased risk of initial and recurrent venous thromboembolism (VTE). Several factors have been found to increase the risk of deep vein thrombosis (DVT) in cancer patients both during the first days after the operation and after discharge from hospital. Although, in general, thromboprophylaxis is provided to cancer patients after surgery, the length of time these patients require prophylaxis has not yet been established. Autopsy series, clinical series, and clinical trials indicate that up to about 40% of VTE occurs post discharge. General surgical patients undergoing major abdominal surgery require VTE prophylaxis, and prolonged thromboprophylaxis should be considered in the post-discharge period in high-risk patients, particularly those with cancer. Evidence from studies in general and orthopedic surgery show that prolonged prophylaxis reduces the number of thromboembolic events after discharge from hospital. Prophylaxis should be simple, safe, and effective and should be administered easily to allow continuation of therapy after discharge. Low-molecular-weight heparins are potentially the most suitable agents for long-term thromboprophylaxis in cancer patients.