Agnes Y.Y. Lee

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update 2014

PURPOSE To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts. RESULTS Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations. RECOMMENDATIONS Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.

Venous Thromboembolism and Cancer: Risks and Outcomes

Abstract Cancer and its treatments are well‐recognized risk factors for venous thromboembolism (VTE). Evidence suggests that the absolute risk depends on the tumor type, the stage or extent of the cancer, and treatment with antineoplastic agents. Furthermore, age, surgery, immobilization, and other comorbid features will also influence the overall likelihood of thrombotic complications, as they do in patients without cancer. The role of hereditary thrombophilia in patients with cancer and thrombosis is still unclear, and screening for this condition in cancer patients is not indicated. The most common malignancies associated with thrombosis are those of the breast, colon, and lung, reflecting the prevalence of these malignancies in the general population. When adjusted for disease prevalence, the cancers most strongly associated with thrombotic complications are those of the pancreas, ovary, and brain. Idiopathic thrombosis can be the first manifestation of an occult malignancy. However, intensive screening for cancer in patients with VTE often does not improve survival and is not generally warranted. Independently of the timing of cancer diagnosis (before or after the VTE), the life expectancy of cancer patients with VTE is relatively short, because of both deaths from recurrent VTE and the cancer itself. Patients with cancer and acute VTE who take anticoagulants for an extended period are at increased risk of recurrent VTE and bleeding. A recent randomized trial, the Randomized Comparison of Low Molecular Weight Heparin versus Oral Anticoagulant Therapy for Long‐Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) study, showed that low molecular weight heparin may be a better treatment option for this group of patients. The antineoplastic effects of anticoagulants are being actively investigated with promising preliminary results. (Circulation. 2003;107:I‐17‐I‐21.)

Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous Thromboembolism

PURPOSE Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism. PATIENTS AND METHODS Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups. RESULTS During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02). CONCLUSION The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.

Incidence, Risk Factors, and Outcomes of Catheter-Related Thrombosis in Adult Patients With Cancer

PURPOSE Thrombosis of long-term central venous catheters (CVC) is a serious complication that causes morbidity and interrupts the infusion of chemotherapy, intravenous medication, and blood products. We performed a prospective study to examine the incidence, risk factors, and long-term complications of symptomatic catheter-related thrombosis (CRT) in adults with cancer. PATIENTS AND METHODS Consecutive patients with cancer, undergoing insertion of a CVC, were enrolled and prospectively followed while their catheter remained in place plus 4 subsequent weeks or a maximum of 52 weeks, whichever came first. Patients with symptomatic CRT were followed for an additional 52 weeks from the date of CRT diagnosis. The end points were symptomatic CRT, symptomatic pulmonary embolism (PE), postphlebitic syndrome, and catheter life span. RESULTS Over 76,713 patient-days of follow-up, 19 of 444 patients (4.3%) had symptomatic CRT in 19 of 500 catheters (0.3 per 1,000 catheter-days). The median time to CRT was 30 days and the median catheter life span was 88 days. Significant baseline risk factors for CRT were: more than one insertion attempt (odds ratio [OR] = 5.5; 95% CI, 1.2 to 24.6; P = .03); ovarian cancer (OR = 4.8; 95% CI, 1.5 to 15.1; P = .01); and previous CVC insertion (OR = 3.8; 95% CI, 1.4 to 10.4; P = .01). Nine of the 19 CRT patients were treated with anticoagulants alone, eight patients were treated with anticoagulants and catheter removal, while two patients did not receive anticoagulation. None had recurrent CRT or symptomatic PE. Postphlebitic symptoms were infrequent. CONCLUSION In adults with cancer, the incidence of symptomatic CRT is low and long-term complications are uncommon.

Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients

Summary.  Background: Cancer patients with venous thromboembolism (VTE) are at high risk of recurrent VTE despite standard anticoagulation. To date, very little published literature is available to guide the treatment of cancer patients with recurrent VTE. Objectives: To evaluate the benefit and risk of low molecular weight heparin (LMWH) dose escalation in cancer patients with recurrent VTE. Patients and methods: This was a retrospective cohort study of consecutive cancer outpatients referred for management of a symptomatic, recurrent VTE while receiving an anticoagulant. Confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH, or initiation of therapeutic dose LMWH in patients who were taking a vitamin K antagonist (VKA). All patients were followed for a minimum of 3 months after the index recurrent VTE unless they died during this period. Results: Seventy cancer patients with a recurrent VTE despite ongoing anticoagulation were included. At the time of the recurrence, 67% of patients were receiving LMWH, and 33% were receiving a VKA. A total of six patients [8.6%; 95% confidence interval (CI) 4.0–17.5%] had a second recurrent VTE during the 3‐month follow‐up period, at an event rate of 9.9 per 100 patient‐years (95% CI 2.0–17.8%). Three patients (4.3%; 95% CI 1.5–11.9%), or 4.8 per 100 patient‐years (95% CI 0.0–10.3%) of follow‐up, had bleeding complications. The median time between the index recurrent VTE to death was 11.4 months (range, 0–83.9 months). Conclusions: Cancer patients with recurrent VTE have a short median survival. Escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight‐adjusted doses of LMWH or a VKA.

Clinical utility of a rapid whole-blood D-dimer assay in patients with cancer who present with suspected acute deep venous thrombosis

Venous thromboembolism is a common complication that contributes to morbidity and mortality in patients with cancer (1, 2). An accurate and efficient diagnostic approach for confirming or excluding venous thrombosis in this subgroup is needed because it represents approximately 20% of all patients in whom deep venous thrombosis or pulmonary embolism is diagnosed (3-5). Noninvasive studies are the diagnostic tools of choice for initial screening for deep venous thrombosis because clinical diagnosis of this condition is inaccurate and because contrast venography, the reference standard, has associated morbidity and is costly. Although studies evaluating the accuracy of noninvasive diagnostic methods have included patients with cancer, it is not known whether these tests are as accurate in this subgroup (6, 7). Both the cancer and its treatments may reduce the accuracy of these tests. For example, extrinsic venous compression by tumor mass may cause false-positive results on impedance plethysmography and compression ultrasonography. In support of these concepts, the one study evaluating diagnostic tests for deep venous thrombosis in patients with cancer demonstrated that impedance plethysmography was less sensitive and specific in these patients than in patients without cancer (8). One of the most promising noninvasive methods for the diagnosis of deep venous thrombosis is d-dimer testing. d-dimer is a plasmin-derived degradation product of cross-linked fibrin whose levels are elevated in the plasma of patients with acute thrombosis and other prothrombotic or inflammatory conditions (9-11). Numerous commercial d-dimer assays are available, and their utility for excluding venous thromboembolism has been established (12-16). The SimpliRED assay (Agen Biomedical, Ltd., Brisbane, Australia) is a rapid d-dimer test that can be performed at the bedside by using 10 L of whole blood obtained from a capillary or venipuncture sample. The test reagent contains a bi-specific antibody formed by conjugating a high-affinity monoclonal antibody against d-dimer with an erythrocyte-binding antibody (17). In the presence of elevated d-dimer levels, erythrocyte agglutination is visible within 2 minutes, indicating a positive test result. In three previous studies, we evaluated the performance of the SimpliRED assay in outpatients presenting with clinically suspected deep venous thrombosis (15, 18, 19). The first study, which used contrast venography as the reference standard to diagnose deep venous thrombosis, demonstrated that the sensitivity, specificity, positive predictive value, and negative predictive value of this assay were 89%, 77%, 56%, and 95%, respectively (18). Other investigators have reported similarly high negative predictive values for this assay (20-22). In our subsequent two studies, d-dimer test results were used to make management decisions in patients with suspected deep venous thrombosis. These studies demonstrated the safety of withholding anticoagulants in patients who had a negative d-dimer test result and a low clinical probability of deep venous thrombosis or a negative d-dimer test result with a normal impedance plethysmogram (15, 19). However, these findings may not apply to patients with cancer for two reasons. First, because patients with cancer can have elevated plasma d-dimer levels in the absence of thrombosis, the specificity of the test may be lower (9-11). Second, because the prevalence of thrombosis is higher in patients with cancer than in those without cancer (1, 2), the predictive values of d-dimer testing may differ in the two patient populations (23, 24). To determine the accuracy and utility of the SimpliRED whole-blood d-dimer assay in patients with cancer, we performed a retrospective analysis of our three studies to compare the performance of this assay in patients with and those without cancer. Methods Patients Patients included in this retrospective analysis participated in three prospective studies conducted between 1992 and 1997 in the outpatient thrombosis units of two tertiary care hospitals in Hamilton, Ontario, Canada (15, 18, 19). In these studies, the accuracy and utility of the SimpliRED assay, in combination with impedance plethysmography or clinical assessment, were evaluated in consecutive outpatients with suspected deep venous thrombosis. These patients were referred directly from local general practitioners or oncologists from the Hamilton Regional Cancer Centre. All patients with a clinically suspected first episode of deep venous thrombosis were eligible. The number of patients, the exclusion criteria, and the reference diagnostic strategies (including venography, serial noninvasive studies, and clinical outcome) in these three studies are listed in Table 1. Table 1. Summary of Three Prospective Studies Evaluating the Performance of the SimpliREDd-dimer Assay in the Diagnosis of Deep Venous Thrombosis d-dimer testing was performed in all eligible, consenting patients at presentation. In the first study, all patients underwent impedance plethysmography and contrast venography (18); in the two subsequent studies, patients were managed on the basis of a priori diagnostic algorithms designed to assess the safety of withholding anticoagulants in patients with negative results on screening tests (18, 19). In these management studies, patients with concordant negative results (negative d-dimer test results and normal impedance plethysmograms or negative d-dimer test results and low clinical pretest probability of deep venous thrombosis) underwent no further testing. Anticoagulants were withheld, and these patients were followed prospectively for 3 months for development of venous thromboembolism. Patients with other combinations of initial test results (discordant results or concordant positive results) and those presenting with symptoms of thromboembolism during follow-up underwent compression ultrasonography, venography, or both to establish a definitive diagnosis. Patients were categorized as positive for thrombosis if deep venous thrombosis was confirmed by objective testing at presentation or during follow-up. All other patients were classified as negative for thrombosis. In all three studies, cancer status was recorded at enrollment and before diagnostic testing. Patients were considered to have active cancer if they had received a diagnosis of cancer, or had received treatment for cancer, in the 6 months before study enrollment; were receiving active or adjuvant treatment for cancer; or had recurrent or metastatic disease at the time of presentation. Patients in whom cancer was diagnosed after study enrollment were not considered to have active cancer at presentation. Patient Data Criteria To minimize bias, a priori criteria were used for data retrieval and analysis. Only data from patients whose initial d-dimer test result and final deep venous thrombosis status were recorded in the original databases were included. Patients whose cancer status was not confirmed on chart review were excluded from this analysis. To confirm cancer status and to obtain more information on cancer history, patient charts from the Hamilton Regional Cancer Centre and the thrombosis units were reviewed. A data collection sheet was developed a priori to facilitate and standardize information retrieval. Information collected included the type and extent of cancer at study enrollment, the time interval between cancer diagnosis and presentation with suspected deep venous thrombosis, and whether the patient was receiving cancer treatment (chemotherapy, hormonal therapy, radiation therapy, or combination therapy). To simplify information about the extent of cancer, three categories were used: localized or early disease, recurrent or metastatic disease, and other (for hematologic and central nervous system disease). Charts were reviewed independently by two reviewers who were blinded to d-dimer test results and final deep venous thrombosis status. Statistical Analysis Patients were analyzed according to their cancer status at the time of study enrollment. Patients in whom cancer was diagnosed after enrollment were considered patients without cancer for the purposes of analysis. To compare the performance of the d-dimer assay in patients with cancer and those without cancer, the sensitivity, specificity, positive predictive value, and negative predictive value were determined separately in the two patient groups (23, 24). Similarly, the likelihood ratios for a positive test result and a negative test result were calculated (23, 25). To combine the study-specific results overall and within the target groups, a simple summation across studies was used to compute the diagnostic indices. This provides the mean of the study-specific and group-specific estimates weighted by the number of patients in each of the studies or groups. For each index, 95% CIs were computed by using the exact binomial distribution for the proportional-type measures and the normal approximation based on the logarithm of the ratio of two proportions for the likelihood ratio measures. The formulas used to calculate the diagnostic indices are shown in Figure 1. Figure 1. Formulas for sensitivity, specificity, predictive values, and likelihood ratios. By using simple summation values, the relative risk for deep venous thrombosis in the presence of cancer was calculated as the ratio of the prevalence of deep venous thrombosis in patients with cancer to the prevalence in patients without cancer. The 95% CI was calculated by using the normal approximation based on the logarithm of the ratio of two proportions. The meta-analytic method used to compare the cancer and noncancer groups differed according to the type of index. For the five proportion measures (prevalence, sensitivity, specificity, positive predictive value, and negative predictive value), the differences between the proportions for each study were weighted by the reciprocal

A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy.

Context Because d-dimer levels increase with pregnancy d-dimer testing is thought to be less accurate for excluding venous thromboembolism in pregnant women than in nonpregnant women. Contribution In this observational, cross-sectional study of 149 pregnant women with suspected deep venous thrombosis (DVT), 13 women (8.7%) had documented DVT. All 13 women with DVT had a positive result on the SimpliRED d-dimer assay (sensitivity, 100% [95% CI, 77% to 100%]). Cautions The lower bound of the 95% CI for the sensitivity of the SimpliRED assay was relatively low (77%). Caution is indicated when the assay is negative and clinical suspicion is relatively high. Implications The SimpliRED assay appears to be as useful for evaluating suspected DVT in pregnant women as in nonpregnant women. A normal result excludes the diagnosis. The Editors Venous thromboembolism (VTE) remains a major cause of maternal morbidity and mortality in developed countries (15), and deep venous thrombosis (DVT) is its most common manifestation. Although the overall incidence of VTE among pregnant women is lowfewer than 1 per 1000 pregnancies (5, 6)this represents a 3- to 4-fold increased risk for VTE compared with age-matched nonpregnant women. As in nonpregnant women, clinical assessment alone is inaccurate for the diagnosis of DVT in symptomatic pregnant patients. The diagnosis of DVT in pregnant patients is further confounded by the frequent occurrence of nonthrombotic causes of leg swelling and pain and the lack of studies evaluating the accuracy of diagnostic testing for DVT. The primary diagnostic tool for DVT is compression ultrasonography (7). This test has been validated as highly sensitive and specific for detecting clinically important DVT in nonpregnant persons. However, the test does not reliably detect isolated iliac vein thrombosis, which is thought to occur relatively frequently during pregnancy (8, 9), or calf vein thrombosis (7). In addition to compression ultrasonography, diagnostic algorithms involving the assessment of clinical pretest probability and d-dimer testing have been developed to guide clinicians in the management of nonpregnant patients suspected of having DVT (1013). These algorithms call for d-dimer testing before the use of compression ultrasonography to stratify patients into those who do and do not require further diagnostic testing. These studies have improved the clinicians ability to accurately diagnose DVT at presentation (1013). Unfortunately, none of the pivotal studies that provided the evidence to generate the algorithms included pregnant patients suspected of having DVT (1013). Compression ultrasonography has been widely adopted as the diagnostic test of choice in pregnant women (14) because of its accuracy in the nonpregnant population and its relative safety with respect to the fetus. The use of d-dimer testing (with or without assessment of the clinicians earlier impression to determine pretest probability) has not been studied in pregnant women suspected of having DVT. In nonpregnant patients, a normal d-dimer test result excludes DVT when combined with either a low pretest probability (as assessed by using a structured clinical prediction rule) or a normal result on compression ultrasonography (1013). d-Dimer levels increase as a normal pregnancy progresses and spike when such conditions as placental abruption or preeclampsia complicate a pregnancy (15, 16). Consequently, the d-dimer test is likely to have lower specificity during pregnancy and therefore produce more false-positive results. Several studies (1719), including one of our own (17), have investigated the performance in asymptomatic pregnant women of various d-dimer assays that were previously validated for VTE diagnosis in nonpregnant patients (20, 21). Both rapid enzyme-linked immunosorbent assay (ELISA) d-dimer tests and latex agglutination tests, at current cutoff values, demonstrated limited diagnostic usefulness in pregnant women suspected of having DVT. In the case of the rapid ELISA, most asymptomatic pregnant women had d-dimer levels that exceeded the reference limit (<280 ng/mL) after 16 weeks of gestation (18). In the case of 1 latex agglutination assay, only 22% of women in the second trimester and none in the third trimester had levels less than the reference limit of 0.5 mg/L (19). In contrast, results on the SimpliRED assay (Agen Biomedical, Brisbane, Australia) were negative in at least 75% of pregnant women without DVT in the first 2 trimesters of pregnancy and in half of the women by the third trimester. In addition to having higher specificity in pregnancy, the SimpliRED assay is relatively easy to perform. Whole blood is mixed with a conjugate of monoclonal antibody to d-dimer linked to a monoclonal antibody, which binds to the erythrocyte surface. The conjugate will coat the erythrocytes, causing agglutination if d-dimer levels are high (22). The presence or absence of agglutination can be interpreted by experienced personnel and the results made available in minutes. Because the SimpliRED assay has a relatively high negative predictive value for DVT in nonpregnant patients (20), has a relatively low rate of false-positive results in asymptomatic pregnant patients (17), and is easy to use (there is no need for specialized equipment), we assessed the accuracy of this assay for excluding DVT and investigated its clinical utility in pregnant women suspected of having DVT. Methods Study Sample Consecutive pregnant women presenting to 5 Canadian centers between March 2000 and November 2005 who were suspected of having DVT were potentially eligible for the study. The 5 centers were Womens College Hospital, Toronto (center 1); Hamilton Health Sciences, McMaster University Medical Center Site (center 2); Henderson Hospital Site (center 3); St. Josephs Healthcare Centre, Hamilton (center 4); and Ottawa Hospital Civic and General Campuses, Ottawa (center 5). The Hamilton and Ottawa centers are tertiary referral sites for thrombosis; the Toronto site, McMaster, St Josephs, and the Ottawa sites are tertiary referral centers for pregnant women. Patients with 1 or more of the following were excluded: a history of VTE, treatment with full-dose anticoagulation for more than 24 hours, concomitant symptoms consistent with pulmonary embolism (PE), inability or unwillingness to return for follow-up, geographic inaccessibility, and failure of patient or attending physician to provide consent. Study Flow The protocol was reviewed and approved by the ethics research boards of all participating centers. Written informed consent was obtained from all study participants. All patients had compression ultrasonography of the symptomatic legs at presentation. Compression ultrasonography was performed with gentle compression of the deep veins of the legs, including the common femoral, the superficial femoral, the popliteal, and the calf trifurcation. If isolated iliac vein thrombosis was suspected, the iliac vein was visualized by direct imaging and Doppler flow. If the result of initial compression ultrasonography was negative, some patients had repeated compression ultrasonography on days 3 and 7, based on the clinicians standard of practice. Deep venous thrombosis was diagnosed on the basis of a noncompressible venous segment and, for the iliac veins, the absence of flow in the iliac vein or the presence of a visible thrombus by B-mode imaging. All patients with DVT were treated with unfractionated or low-molecular-weight heparin. Patients whose result on compression ultrasonography was normal had anticoagulant therapy withheld and underwent clinical follow-up for at least 3 months to ensure the correctness of the initial exclusion of DVT. This approach has been used to categorize patients as DVT positive or DVT negative by several groups (1013), including our own, in the validation of many diagnostic tests for DVT. Blood for d-dimer testing was drawn at enrollment, and the SimpliRED assay was performed within 1 hour of collection by trained laboratory technicians who were blinded to the clinical status of the patient and the results of other diagnostic testing for DVT. Because structured clinical prediction rules have not been validated in pregnancy (21), we categorized the pretest probability of each patient as low, intermediate, or high on the basis of the clinicians earlier impression. These assessments were performed by experienced clinicians before the results of other diagnostic tests were known. All patients recruited into the study were advised to return on an emergency basis if clinical symptoms consistent with DVT or PE developed. Such patients were then investigated with appropriate diagnostic testing consistent with the local centers usual practice. Statistical Analysis Patients were categorized as DVT positive if the results of their diagnostic compression ultrasonography at presentation were positive or if they had symptomatic DVT or PE on follow-up. Patients with negative ultrasonography results at presentation and no VTE in follow-up were categorized as DVT negative. The test characteristics (sensitivity, specificity, and negative predictive value) and likelihood ratios of the SimpliRED assay and their corresponding 95% CIs were calculated on the basis of the d-dimer test result at the time of initial presentation and the presence or absence of diagnosed DVT in the patient over the duration of the study. Role of the Funding Sources Partial funding was provided over 2 years by the Heart and Stroke Foundation of Ontario (grant NA 5048) to recruit patients into the study. The SimpliRED assay kits were provided by Agen Biomedical, Brisbane, Australia. The company had no role in the design or conduct of the study or the decision to submit the paper for publication. Results A total of 149 pregnant women were enrolled over the study period. Suspicion for DVT in these patients was almost always triggered by 1 or more of th

Cancer and thromboembolic disease: pathogenic mechanisms

Almost all types of cancer are associated with an activation of coagulation. However, elevation of haemostatic markers of coagulation does not predict venous thrombosis. Multiple and interdependent processes between the tumour and the patient induce a hypercoagulable state. Tumour procoagulant activity, host inflammatory responses and extrinsic factors are involved. Tumour cells express the procoagulants, tissue factor and cancer procoagulant. They also release inflammatory cytokines and vascular endothelial growth factor, substances that enhance procoagulant activity and angiogenesis. Tumour-induced coagulation is intrinsically involved with tumour growth, angiogenesis and metastasis.

Risk factors for catheter-related thrombosis (CRT) in cancer patients: a patient-level data (IPD) meta-analysis of clinical trials and prospective studies

Background: Knowledge of independent, baseline risk factors for catheter‐related thrombosis (CRT) may help select adult cancer patients who are at high risk to receive thromboprophylaxis. Objectives: We conducted a meta‐analysis of individual patient‐level data to identify these baseline risk factors. Patients/Methods: MEDLINE, EMBASE, CINAHL, CENTRAL, DARE and the Grey literature databases were searched in all languages from 1995 to 2008. Prospective studies and randomized controlled trials (RCTs) were eligible. Studies were included if original patient‐level data were provided by the investigators and if CRT was objectively confirmed with valid imaging. Multivariate logistic regression analysis of 17 prespecified baseline characteristics was conducted. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results: A total sample of 5636 subjects from five RCTs and seven prospective studies was included in the analysis. Among these subjects, 425 CRT events were observed. In multivariate logistic regression, the use of implanted ports as compared with peripherally implanted central venous catheters (PICCs), decreased CRT risk (OR, 0.43; 95% CI, 0.23–0.80), whereas past history of deep vein thrombosis (DVT) (OR, 2.03; 95% CI, 1.05–3.92), subclavian venipuncture insertion technique (OR, 2.16; 95% CI, 1.07–4.34) and improper catheter tip location (OR, 1.92; 95% CI, 1.22–3.02), increased CRT risk. Conclusions: CRT risk is increased with use of PICCs, previous history of DVT, subclavian venipuncture insertion technique and improper positioning of the catheter tip. These factors may be useful for risk stratifying patients to select those for thromboprophylaxis. Prospective studies are needed to validate these findings.

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.