Martha L Louzada

Development of a Clinical Prediction Rule for Risk Stratification of Recurrent Venous Thromboembolism in Patients with Cancer: Associated Venous Thromboembolism

Background— Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. Methods and Results— The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between −3 and 3 score points. Patients with a score ⩽0 had low risk (⩽4.5%) for recurrence and patients with a score >1 had a high risk (≥19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. Conclusions— By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Efficacy of Low- molecular- weight- heparin versus Vitamin K antagonists for long term treatment of cancer-associated venous thromboembolism in adults: A systematic review of randomized controlled trials

BACKGROUND Patients with malignancy have a 4-fold increase in the risk of developing a venous thrombosis and a 3-fold increase in risk of bleeding. Both low-molecular-weight-heparin (LMWH) and vitamin K antagonists (VKA) have been used for treatment of cancer-associated thrombosis. However, the best anticoagulation approach remains a matter of debate. OBJECTIVE In adult patients with cancer and an acute venous thromboembolic event we sought to determine the rates of recurrent venous thromboembolism (VTE) and major hemorrhage when treated with prolonged LMWH therapy compared to vitamin-K antagonists. PATIENTS/METHODS A systematic literature search strategy was used to identify potential trials on MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Medline in-process using an OVID interface. Risk assessment of bias of randomized controlled trials (RCTs) was performed according to the Cochrane Collaboration-Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome measure was symptomatic VTE recurrence rate during the anticoagulation period. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated using random -effects and fixed-effects model. RESULTS Five articles met our inclusion criteria. All compared LMWH and VKA for secondary prevention of VTE. The pooled RR of VTE recurrence was 0.53 (95% CI: 0.36-0.76; p=0.007). The pooled RR of major bleeding was 0.98 (95% CI: 0.49-1.93, p=0.95). Minor bleeding events and all cause mortality were similar between the 2 intervention arms. CONCLUSIONS The results of our review suggest that the long term use of LMWH after the acute first week of treatment is superior to VKAs for secondary prevention of venous thromboembolism in adult patients with cancer.

Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies.

Patients with cancer-associated venous thromboembolism (VTE) should be treated with low molecular weight heparin. The ideal duration of anticoagulation in this population is unknown. It is important to evaluate whether there is variation in susceptibility for recurrent VTE according to malignancy characteristics. In this systematic review we sought to evaluate cancer characteristics that may influence the risk for VTE recurrence and the success of anticoagulation in patients with cancer-associated VTE. A systematic literature search strategy identified potential studies on MEDLINE, Embase, the Cochrane Register of Controlled Trials, MEDLINE In-Process and other nonindexed citations using the Ovid interface. There was no restriction to study design or language. No randomized controlled trials fulfilled our inclusion criteria. We included four retrospective and six prospective studies. VTE recurrence rate according to tumour stage suggested an increased risk for patients with metastatic malignancy compared with patients with localized disease (relative risk 1.36; 95% confidence interval 1.06–1.74, P = 0.01). We were unable to pool data to evaluate VTE recurrence according to tumour site and histology. The isolated evaluation of the included studies suggested that younger patients with adenocarcinoma, lung or gastrointestinal malignancy have the highest risk. There is paucity of data regarding detailed malignancy characteristics in patients with cancer-associated VTE. It appears that metastatic malignancy, or adenocarcinoma, or lung malignancy confers a higher risk of VTE recurrence than patients with localized malignancy, nonadenocarcinoma or breast cancer.

Clinical performance of bleeding risk scores for predicting major and clinically relevant non‐major bleeding events in patients receiving warfarin

Oral anticoagulant therapy is associated with an increased risk of hemorrhage, which can be assessed by bleeding risk scores. We evaluated the performance of five validated scores for predicting major and clinically relevant non‐major bleeding events in patients receiving warfarin.

Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review.

BACKGROUND Studies have consistently demonstrated the need for venous thromboembolism (VTE) prophylaxis in patients with newly diagnosed multiple myeloma (NDMM) or relapsed refractory multiple myeloma (RRMM), receiving lenalidomide-based therapy. However, the optimal approach has not yet been established. OBJECTIVE To compare the efficacy of aspirin (ASA) and low molecular weight heparin (LMWH) prophylaxis in patients with myeloma using lenalidomide-based therapy. RESULTS Six studies were included with 1125 adult participants with NDMM or RRMM treated with lenalidomide-based therapy with thromboprophylaxis with ASA or LMWH. Pooled data of studies of NDMM showed that the risk of VTE in patients on ASA was 1.5 per 100 patient-cycles with a total risk of VTE of 98 of 915 (10.7%) [95% CI: 8.86-12.88] compared to 3 of 211 (1.4%) [95% CI: 0.48-4.09] with LMWH in NDMM and RRMM patients. Our study demonstrated a significantly higher VTE risk for patients receiving lenalidomide plus high-dose dexamethasone (RD) on ASA prophylaxis compared to lenalidomide plus low-dose dexamethasone (Rd) [RR=2.5 (95% CI: 1.68-3.96), P<0.0001]. Furthermore, patients who received lenalidomide and dexamethasone alone had a significantly higher risk of VTE compared to those on MPR while on ASA prophylaxis (RR=6.4 [(95% CI: 4.11-9.91), P<0.0001]). CONCLUSION The most frequent thromboprophylaxis option used for myeloma patients on lenalidomide-based therapy is ASA. However, ASA may not confer appropriate thromboprophylaxis in patients using RD, but may be a safe option with MPR. In future studies, the IMWG VTE risk stratification criteria should be validated, incorporating the thromboprophylaxis option accordingly. More studies comparing the efficacy and safety of ASA to LMWH are warranted.

Psychological impact of thrombophilia testing in asymptomatic family members

INTRODUCTION Psychological distress and worry are commonly described as potential consequences of genetic screening for various disorders. Thrombophilia testing may be offered to asymptomatic persons with a family history of venous thrombosis and thrombophilia. Our objectives were to measure the psychological impacts of thrombophilia testing in first degree relatives and to determine if our intervention, a more intensive care strategy to heighten awareness of both risk and symptoms of thrombosis, caused psychological distress. MATERIALS & METHODS First degree relatives of patients with a known thrombophilia and history of venous thrombosis were tested for thrombophilia. The Perceived Risk Questionnaire and validated psychological instruments (POMS-SF; SCL-90-R Somatization subscale) were administered before testing, one week after receiving results and a year later. Thrombophilia carriers were randomized in family clusters to receive Standard Care or the Intensive Care intervention. RESULTS There were 100 carriers who were randomized to Standard (n=48) or Intensive Care (n=52) and 103 non-carriers. One week after receiving results, we did not observe any difference in psychological distress between carriers and non-carriers, with low levels overall. At 1 year, psychological distress scores were similar between the Standard and Intensive Care arms and did not differ from baseline. CONCLUSIONS The results of this pilot study do not support the concern that thrombophilia screening in asymptomatic relatives triggers psychological distress and worry. Furthermore, our intensive educational approach did not appear to induce undue distress. While the positive benefits of thrombophilia screening remain unproven, clinicians should not be deterred from offering screening by the fear of causing psychological harm.

A pilot study to assess the feasibility of a multicenter cluster randomized trial for the management of asymptomatic persons with a thrombophilia.

There is controversy whether asymptomatic first-degree relatives (FDRs) of patients with venous thromboembolism (VTE) and thrombophilia should be screened, followed, and prescribed prophylaxis during risk periods. We recruited consecutive probands with idiopathic VTE and thrombophilia from our thrombosis clinics. Those FDRs with thrombophilia were randomized in family clusters to receive one-time verbal counseling and no organized follow-up or counseling, educational material, reminder aids and follow-up. Only 203 of 1,129 FDRs were eligible and consented. Dropouts were common; 1 FDR (1.7%) developed VTE. VTE risk, ability to treat and prevent were underestimated by the participants. Patients with VTE and thrombophilia and their FDRs are often not interested in thrombophilia testing. Despite education to inform their knowledge, interest and follow-up were less than ideal. The question of the best educational approach in these patients remains unanswered. The value of testing and following asymptomatic carriers of probands with VTE and thrombophilia remains unknown.

A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2)

INTRODUCTION Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. OBJECTIVES To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. MATERIALS AND METHODS Patients ≥18years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15mg oral twice daily for 3weeks, followed by 20mg oral daily for 9weeks. Patients were followed clinically for 12weeks to assess for line function, recurrent VTE and bleeding. RESULTS Seventy patients (47 women) were included, with mean age 54.1years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12weeks. The risk of recurrent VTE at 12weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. CONCLUSIONS Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Screening of Patients with Idiopathic Venous Thromboembolism for Paroxysmal Nocturnal Hemoglobinuria Clones

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thrombosis and marrow failure. Whereas venous and arterial thrombosis is a very common symptom of the disease, the frequency of PNH clones in patients with unexplained venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has not been studied. We conducted a cross sectional study evaluating the presence of PNH clones in patients with prevalent venous thromboembolism using a high sensitivity flow cytometry assay for erythrocytes and neutrophils. Among the 388 patients enrolled in the study one patient had a detectable PNH clone of 0.02% in the neutrophil population (0.26%; 95% CI 0.05 to 1.45) and no detectable erythrocyte clone. We conclude that the presence of PNH clones in patients with idiopathic venous thrombosis is rare. Screening for PNH clones among VTE patients might be better reserved for patients with signs of hemolysis.

Prevention of venous thromboembolism in pregnant patients with a history of venous thromboembolic disease: A retrospective cohort study

BACKGROUND Optimal prophylactic strategies in pregnant women with a history of venous thromboembolism (VTE) are unknown. PATIENTS AND METHODS We conducted a retrospective cohort study of consecutive pregnant patients with a previous VTE history. Patients were followed until 6 weeks postpartum. Patients with a previous unprovoked event (including antepartum VTE) received antenatal prophylaxis, mostly with low dose low molecular weight heparin (LMWH). All patients received prophylaxis for six weeks after delivery. RESULTS We included a total of 199 pregnancies in 142 women. Of these, 147 pregnancies occurred in women with unprovoked or estrogen-related VTE history and 52 pregnancies in women with provoked VTE. There were 8 recurrences in 199 pregnancies (4%; 95%CI: 2.05-7.73), of which 5 were antepartum recurrences (2.5%; 95%CI 1.08-5.75) and 3 were postpartum (1.5%; 95% CI 0.51-4.34). In the unprovoked VTE group there were 7 recurrences (4.7%; 95%CI: 2.32-9.50), whereas in the provoked VTE group there was 1 (1.9%; 95%CI: 0.34-10.12). There was one major bleeding event in a patient not receiving LMWH secondary to placental abruption. CONCLUSION This study suggests that the use of prophylactic doses of LMWH during pregnancy and puerperium, as described in this study, results in low occurrence of ante- and postpartum VTE recurrences in patients with previous VTE. Further studies are required to confirm this observation.