The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish ...medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval CI, 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population.
•The 12-month cumulative incidence of VTE is currently 3% after cancer diagnosis, which is ninefold higher than in the general population.•For the past 2 decades, cancer patients' VTE risk increased threefold overall and sixfold in those using chemotherapy or targeted therapy.
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Background: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. Objectives: To establish ...a common international consensus addressing practical, clinically relevant questions in this setting. Methods: An international consensus working group of experts was set up to develop guidelines according to an evidence‐based medicine approach, using the GRADE system. Results: For the initial treatment of established VTE: low‐molecular‐weight heparin (LMWH) is recommended 1B; fondaparinux and unfractionated heparin (UFH) can be also used 2D; thrombolysis may only be considered on a case‐by‐case basis Best clinical practice (Guidance); vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients Guidance. For the early maintenance (10 days to 3 months) and long‐term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) 1A; idraparinux is not recommended 2C; after 3–6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit‐risk ratio, tolerability, patient preference and cancer activity Guidance. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion Guidance. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12–2 h preoperatively and continued for at least 7–10 days; there are no data allowing conclusion that one type of LMWH is superior to another 1A; there is no evidence to support fondaparinux as an alternative to LMWH 2C; use of the highest prophylactic dose of LMWH is recommended 1A; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding 2B; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy Guidance; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated 2C. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux 1B; for children and adults with acute lymphocytic leukemia treated with l‐asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients Guidance; in patients receiving chemotherapy, prophylaxis is not recommended routinely 1B; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic 1B or lung 2B cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low‐dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear 2C. Special situations include brain tumors, severe renal failure (CrCl < 30 mL min−1), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Conclusions: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.
Background: Although long‐term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC‐related thrombosis ...(CRT) in cancer patients and heterogeneity in clinical practices worldwide. Objectives: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. Methods: An international working group of experts was set up to develop GCPG according to an evidence‐based medicine approach, using the GRADE system. Results: For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non‐randomized prospective studies and one retrospective study examining the efficacy and safety of low‐molecular‐weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting Guidance. The CVC can be kept in place if it is functional, well‐positioned and non‐infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established Guidance. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double‐blind randomized and one non randomized study on thrombolytic drugs and six meta‐analyses of AC and CVC thromboprophylaxis. Type of catheter (open‐ended like the Hickman® catheter vs. closed‐ended catheter with a valve like the Groshong® catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non‐randomized trials, three randomized trials and one meta‐analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended 1A; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium 1A. Conclusion: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.
Summary
Background
D‐dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients.
Objectives
...To analyze the relationships between D‐dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649).
Patients/methods
This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D−dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non‐major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35.
Results
The frequency of VTE was 3.5‐fold greater in patients with high D‐dimer concentrations. Multivariate analysis showed that D‐dimer was an independent predictor of the risk of VTE (odds ratio 2.29 95% confidence interval 1.75–2.98), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D‐dimer group, rivaroxaban was non‐inferior to enoxaparin at day 10 and, unlike the low D‐dimer group, superior to placebo at day 35 (P < 0.001) and days 11–35 (P < 0.001). In both groups, bleeding outcomes favored enoxaparin/placebo.
Conclusions
Elevated baseline D‐dimer concentrations may identify acutely ill, hospitalized medical patients at high risk of VTE for whom extended anticoagulant prophylaxis may provide greater benefit than for those with low D‐dimer concentrations.
Background: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous ...thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double‐blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once‐daily, starting with a half‐dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once‐daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the dabigatran etexilate 220‐mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150‐mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non‐inferior to enoxaparin on the basis of the prespecified non‐inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow‐up. Conclusions: Dabigatran etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.
Abstract Background The Khorana score is a clinical prediction score developed to identify ambulatory cancer patients at high risk of venous thromboembolism (VTE), who may be eligible for ...thromboprophylaxis. This score has been validated in various populations with cancer, but its performance in patients with pancreatic cancer is less clear. Patients and methods This is a single center, retrospective cohort study in which consecutive, ambulatory patients with pancreatic adenocarcinoma, who started neoadjuvant or palliative chemotherapy at our center between 2003 and 2014 were included. At baseline, the Khorana score classified patients as ‘intermediate risk’ (2 points) or ‘high risk’ (≥ 3 points) for VTE. The primary outcome was the composite of objectively confirmed symptomatic or incidental lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE) during 2-year follow-up. Results The study group comprised 178 patients. The mean age was 62 years and 62% had distant metastasis. Overall, 22 of 178 patients (12.4%) developed lower extremity DVT or PE. The estimated cumulative incidence at 6 months was 8.2% in ‘intermediate risk’ patients and 9.5% in the ‘high risk’ patients (subhazard ratio for first 6 months: 1.23; 95% CI: 0.41
–
3.65). At 2 years, the cumulative incidence was higher in ‘intermediate risk’ patients (15.3%) than in ‘high risk’ patients (10.1%). Conclusions In the present study, the Khorana score was not able to discriminate between pancreatic cancer patients at intermediate risk and high risk of VTE. Physicians should have a low threshold of considering thromboprophylaxis in patients with pancreatic cancer given the high absolute VTE risk.
Background: Whether glucocorticoid use contributes to a hypercoagulable state, and thereby enhances the thrombotic risk, is controversial. Objective: We aimed to examine the effects of glucocorticoid ...use on coagulation and fibrinolysis. Methods: MEDLINE and EMBASE databases were searched to identify published studies comparing glucocorticoid treatment with a glucocorticoid‐free control situation. Subjects could be either patients or healthy volunteers. Two investigators independently performed study selection and data extraction. Results were expressed as standardized mean difference, if possible; data were pooled with a random‐effects model. Results: Of the 1967 identified publications, 36 papers were included. In healthy volunteers, a clear rise in factor (F)VII, VIII and XI activity was observed after glucocorticoid treatment, but these data alone provided insufficient evidence to support hypercoagulability. However, during active inflammation, glucocorticoids significantly increased levels of plasminogen activator inhibitor‐1 (PAI‐1), whereas levels of von Willebrand factor (VWF) and fibrinogen decreased. Peri‐operative use of glucocorticoids inhibited the increase in tissue‐type plasminogen activator induced by surgery. Conclusions: The present study showed differential effects of glucocorticoids depending on the clinical situation in which it is given, most likely as a result of their disease modifying properties. Clinical outcome studies are needed to adequately assess the risk‐benefit of glucocorticoid use per population when thrombotic complication is the focus.
In 2012, around 400.000 patients in the Netherlands were treated with Vitamin K Antagonists (VKA) for thromboembolic diseases. Since 2011, non-VKA oral anticoagulants (NOACs) are available. NOACs do ...not require frequent INR monitoring which benefits patients, but also imposes a risk of reduced therapy adherence. The objective of this study is to describe uptake and patient adherence of NOACs in The Netherlands until October 2016.
Prescription data for 247.927 patients across 560 pharmacies were used to describe patient profiles, uptake of NOACs among new naive patients and switch between VKA and NOACs, and calculate therapy adherence as the Proportion of Days Covered (PDC).
During the studied period the share of NOACs in oral anticoagulants has grown to 57% of prescriptions to new patients. More than 70% of new NOAC users were new naive patients and around 26% switched from VKA. The overall share of NOACs among starters is largest in the group of patients of 50-80 years. Calculated compliance rate for NOAC patients shows that 88% of all users are adherent with a PDC higher than 80%.
NOAC have overtaken VKA as the major treatment prescribed to new oral anticoagulant patients, and the number of starters on VKA is decreasing. Patients are generally adherent to NOACs during the implementation phase, the period that the medication is used. Fear for inadherence by itself does not need to be a reason for not prescribing NOACs instead of VKA.
Summary
Introduction
Little is known about the natural history of clot resolution in the initial weeks of anticoagulant therapy in patients with acute pulmonary embolism (PE). Clot resolution of ...acute PE was assessed with either computed tomography pulmonary angiography scan (CT‐scan) or perfusion scintigraphy scan (Q‐scan) after 3 weeks of treatment.
Methods
This was a predefined safety analysis of the Einstein PE study, including PE patients, randomized to either enoxaparin with vitamin K antagonist (VKA) or rivaroxaban. A similar scan as at baseline was repeated after 3 weeks. The percentage of vascular obstruction (PVO) was calculated on the basis of a weighted semiquantitative estimation of obstruction. Clot resolution was assessed blindly by calculating the relative change after 3 weeks.
Results
PE was diagnosed in 264 patients with CT‐scan and in 83 with Q‐scan. Baseline characteristics were similar. At baseline, the mean PVO assessed with CT‐scan (PVO‐CT) and the mean PVO assessed with Q‐scan (PVO‐Q) were both 21% (standard deviation SD 13%) (P = 0.9). The mean relative decrease in PVO was 71% (SD 33%) for PVO‐CT, and 62% (SD 36%) for PVO‐Q (P = 0.02); complete resolution was observed in 44% (116/264; 95% confidence interval CI 38–50%) and 31% (26/83; 95% CI 22–42%) with CT‐scan and Q‐scan, respectively (P = 0.04). No difference in clot resolution between enoxaparin/VKA and rivaroxaban was found.
Conclusion
In patients with acute PE, only 3 weeks of anticoagulant treatment leads to complete clot resolution in a considerable proportion of patients, and normalization is more often observed with CT‐scan than with Q‐scan.
Essentials
Cancer patients are at high risk of venous thromboembolism (VTE).
In this study, cases and controls were cancer patients who did or did not develop VTE.
von Willebrand factor (VWF) levels ...were higher if compared with controls and correlated with cancer stage.
VWF and ADAMTS‐13 are associated with the occurrence of VTE in cancer.
Summary
Background
Patients with cancer are at high risk of venous thromboembolism (VTE). ADAMTS‐13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE.
Objectives
The aim of this study was to search for an association between the levels of VWF and ADAMTS‐13 and VTE in patients with cancer and to compare current scoring systems for prediction of VTE before and after addition of these parameters.
Patients/Methods
In a case–control study, in which patients with recently diagnosed cancer were followed‐up for 6 months, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, and type and stage of cancer. We measured VWF, ADAMTS‐13 (activity and antigen), P‐selectin, D‐dimer and F1 + 2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P‐selectin and D‐dimer levels.
Results
VWF levels were significantly higher in cases when compared with controls (326 ± 185% vs. 242 ± 158%) and correlated with advanced stage of cancer: localized, 185 142; 222; locally advanced, 240 146; 257; metastatic, 267 153; 324 (mean interquartile range). The addition of two biomarkers, ADAMTS‐13 activity and F1 + 2 levels, to the Khorana score improved receiver operating curves.
Conclusions
von Willebrand factor and ADAMTS‐13 are associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS‐13 and F1 + 2 levels to the Khorana score considerably increases the predictive value for VTE.
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