Comparison of rivaroxaban and dalteparin for the long-term treatment of venous thromboembolism in patients with gynecologic cancers.

OBJECTIVES: Two randomized, controlled studies comparing outcomes in patients treated with direct oral anticoagulants or low-molecular weight heparin for cancer-associated venous thromboembolism (VTE) have previously been performed. However, gynecologic cancers accounted for approximately 10% of the study populations. We compared the outcomes of patients with primary gynecological cancers who were treated for cancer-associated VTE with either rivaroxaban or dalteparin. METHODS: The 162 eligible patients with gynecologic cancers who were treated with either dalteparin (n=60) or rivaroxaban (n=102) were reviewed. The primary outcome was a composite event, which included recurrence or clinically relevant bleeding events during the therapeutic period. Secondary outcomes were recurrence, clinically relevant bleeding events, and mortality. RESULTS: During the therapeutic period, there were no significant differences between the groups in the proportion of composite events, recurrence, or clinically relevant bleeding. Multivariate analysis using the Cox proportional hazards model also showed no significant difference in the number of composite events and clinically relevant bleeding between the groups. In the rivaroxaban group, 44.0% of patients experienced gastrointestinal bleeding and 24.0% experienced urinary tract bleeding. In the dalteparin group, bleeding was most common in the urinary tract (44.4%) and at the injection site (22.2%). CONCLUSION: In this study, although there were no significant differences in effectiveness or safety between the rivaroxaban and dalteparin groups, rivaroxaban use was associated with a higher rate of clinically relevant bleeding than dalteparin. Therefore, caution should be taken when prescribing rivaroxaban for gynecologic cancer-associated VTE and bleeding events should be carefully monitored.

[Direct oral anticoagulants in the treatment of cancer-associated thrombosis]. / Anticoagulants oraux directs dans le traitement des événements thrombo­emboliques veineux liés au cancer.

The use of direct oral anticoagulants (DOACs) has been largely -implemented in the management of venous thromboembolic disease in non-cancer patients. In cancer-associated thrombosis, low molecular weight heparins (LMWHs) and especially dalteparin have long been the reference standard therapy. Following the publication of two randomised trials comparing edoxaban and rivaroxaban to -dalteparin, DOACs now represent an alternative with an interesting efficacy and safety profile. Moreover, they offer the comfort of an oral administration and a lower cost. In patients with gastrointestinal or genitourinary cancers however, a higher bleeding risk has been shown with DOACs. LMWHs thus remain the treatment of choice in this group of patients.

L'utilisation des anticoagulants oraux directs (ACOD) pour le traitement de la maladie thromboembolique veineuse (MTEV) chez les patients sans cancer est déjà largement implémentée. En cas de MTEV liée au cancer, les héparines de bas poids moléculaire (HBPM) et en particulier la daltéparine, ont longtemps ­représenté le traitement de référence. Suite à la publication de deux études randomisées récentes comparant l'édoxaban et le rivaroxaban à la daltéparine, les ACOD se sont révélés être une alternative efficace, avec un profil de sécurité satisfaisant, ­offrant par ailleurs le confort d'une administration orale et un coût moindre. Toutefois, en raison d'un risque hémorragique ­accru sous ACOD chez les patients avec un cancer de localisation digestive ou urogénitale, les HBPM restent le traitement de choix dans ce groupe de patients.

Oral anticoagulation is preferable to injected, but only if it is safe and effective: An interview study of patient and carer experience of oral and injected anticoagulant therapy for cancer-associated thrombosis in the select-d trial.

BACKGROUND: Cancer patients have a four- to fivefold greater risk of thrombosis than the general population. Recommended treatment for cancer-associated thrombosis is 3-6 months of low-molecular-weight heparin. The 'select-d' trial is an open-label, randomised, multi-centre pilot trial in patients with cancer-associated thrombosis, utilising dalteparin (low-molecular-weight heparin) versus rivaroxaban (a direct oral anticoagulant), to assess effectiveness and safety. AIM: To explore patient and informal carers' experiences of cancer-associated thrombosis and their experience and understanding of the risk-benefit of thrombosis treatment. DESIGN: Qualitative substudy of the select-d trial, using semi-structured interviews. Interviews were audio-recorded and transcribed. Data were analysed using Framework Analysis. PARTICIPANTS: Participants were purposively sampled ( n = 37 patients; 46% male; age 40-89; 9 with carer present). RESULTS: Three themes were found: experience of cancer-associated thrombosis, experience of anticoagulation and risk-benefit balance of the two modes of administration. Some were shocked by their thrombosis diagnosis (most were unaware of their risk), but others found it insignificant compared with cancer. Most patients found tablets more convenient, but injections were acceptable in the context of having cancer. While most were happy to follow medical advice, others weighed preference on the basis of effectiveness. CONCLUSION: Lack of awareness of thrombosis risk is concerning; cancer patients must be informed to enable prompt help-seeking. Tablets could provide a welcome choice for patients if there is equivalent risk-benefit to injected anticoagulants. Patients trust their clinicians to tailor their treatment. Future research could explore the effect of routine information giving about the risk of thrombosis.

[Treatment of cancer-associated venous thromboembolism]. / Terapia del tromboembolismo venoso associato al cancro.

Most clinical practice guidelines recommend low molecular weight heparin for the treatment of venous thromboembolism (VTE) in cancer patients. In the Hokusai VTE Cancer study, 1050 patients with cancer and acute VTE were randomized to oral edoxaban or subcutaneous dalteparin for at least 6 months and up to 12 months. Edoxaban was non-inferior to dalteparin with respect to the composite outcome of recurrent VTE and major bleeding. The rate of recurrent VTE was numerically lower, but the rate of major bleeding was significantly higher with edoxaban. The frequency of severe major bleeding was similar with edoxaban and dalteparin. The difference in major bleeding was mainly driven by a higher rate of upper gastrointestinal bleeding with edoxaban, especially in patients with gastrointestinal cancer. The pilot Select-D study randomized 406 patients with cancer and VTE to rivaroxaban or dalteparin for 6 months. Recurrent VTE was reduced, while both major and clinically relevant non major bleeding were significantly increased with rivaroxaban. Bleeding mostly involved the gastrointestinal tract and occurred in patients with gastroesophageal cancer. While waiting for ongoing studies on direct oral anticoagulants, the results of the Hokusai VTE Cancer suggest that edoxaban may represent a valuable alternative to low molecular weight heparin for the treatment of cancer-associated VTE. In patients with gastrointestinal cancer, the use of edoxaban requires careful benefit-risk weighting, taking into consideration patient's preferences.

Treatment of Cryptogenic Stroke with Active Cancer with a New Oral Anticoagulant.

BACKGROUND: Low-molecular weight heparin (LMWH) was shown to be effective and safe in treating venous thromboembolism, and generally used for stroke in cancer patients, but its effects on stroke are unclear. We compared clinical outcomes between LMWH and new oral anticoagulant (NOAC) in patients with cancer-related stroke. METHODS: We enrolled patients with cryptogenic ischemic stroke with active cancer who were treated with LMWH or NOAC between May 2012 and June 2015. The clinical outcomes, including early neurologic deterioration, early radiologic recurrence, 3-month modified Rankin scale score, 90-day mortality, cardio-cerebrovascular recurrence, and bleeding complications, were compared. RESULTS: Among 48 patients, 7 patients were treated with NOAC, and the remaining 41 patients with LMWH. Overall, the participants presented poor outcomes, including 20 (42%) early neurologic deteriorations, 28 (58%) early radiologic recurrences, 34 (71%) poor modified Rankin scale scores, 27 (56%) 90-day mortality events, 24 (50%) cardio-cerebrovascular recurrences, and 18 (38%) bleeding complications, that led to a change or temporary hold in medication in 12 cases. No statistical differences were found between the 2 groups in terms of demographic, clinical, or cardiovascular risk factors and clinical outcomes. CONCLUSIONS: NOAC showed the similar clinical outcomes and safety compared with LMWH in the treatment of cryptogenic ischemic stroke in active cancer patients.

Treatment for superficial infusion thrombophlebitis of the upper extremity.

BACKGROUND: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Improved angiogenesis and healing in crush syndrome by fibroblast growth factor-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles.

BACKGROUND: We produced fibroblast growth factor (FGF)-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles (FGF-2 + F/P NPs). The purpose of this study was to evaluate the effectiveness of the local administration of FGF-2 + F/P NPs on repairing crush syndrome (CS)-injured lesions after compression release using a nonlethal and reproducible CS injury rat model. MATERIALS AND METHODS: The hind limbs of the anesthetized rats were compressed for 6 h using 3.6 kg blocks, as previously described. The effects of administering FGF-2 + F/P NPs (group A), F/P NPs alone (group B), FGF-2 alone (group C), and saline (control; group D) were examined. Motor function, surface blood flow in the hind limbs, and the wet/dry weight ratio in the tibialis anterior muscle were examined for 1-28 d after the compression release. Histologic analyses were also performed. RESULTS: At the middle and late stages (3-28 d after the compression release), group A had higher scores in the motor function, improved blood flow, increased number of blood vessels, and faster recovered muscle tissue, compared with the other groups. There was no significant difference in enhanced edema in the tibialis anterior muscle among all groups. CONCLUSIONS: The local administration of FGF-2 + F/P NPs to a CS-injured lesion was effective in repairing damaged muscle tissue after compression release.

Nadroparine blunts lipopolysaccharide-induced hypothermia and behavioral depression in mice.

INTRODUCTION: Despite the use of appropriate antimicrobial therapy and intensive care support, sepsis remains a major cause of morbidity and mortality in surgical clinics. Low-molecular weight heparin treatment may reduce mortality and end-organ failure in sepsis. The purpose of this study was to compare the effects of low-molecular weight heparins such as nadroparine, enoxaparine, and dalteparine on lipopolysaccharide-induced acute phase reaction in mice. METHODS: Lipopolysaccharide was injected intraperitoneally to produce a systemic inflammatory response and septic shock-like effects in adult male BALB/c mice. Mices were treated with low-molecular weight heparins (nadroparine, enoxaparine, dalteparine) and unfractioned heparin in different doses and times. Rectal temperature and spontaneous locomotor activity of the mice were evaluated. RESULTS: Lipopolysaccharide (1 mg/kg, intraperitoneal) produced a hypothermia that occurred 20 minutes after injection. Nadroparine pretreatment (23.75 U/kg, sc) 2 hours before lipopolysaccharide challenge, but not synchronous injection, inhibited the hypothermic response. Pretreatment with equivalent doses of enoxaparine or dalteparine had no effect on the hypothermia. The high dose of lipopolysaccharide (60 mg/kg, intraperitoneal) caused more profound hypothermia and also inhibited spontaneous locomotor activity 24 hours after injection. Synchronous nadroparine administration partially attenuated the hypothermia and significantly abolished the depression of spontaneous locomotor activity. CONCLUSIONS: The results suggest that some low-molecular weight heparins such as nadroparine might be beneficial in high-risk surgical patients because of their potential anti-inflammatory action, in addition to their efficiency in preventing thrombo-embolic complications.

High-dose intravenous dalteparin can be monitored effectively using standard coagulation times.

The objective of this study was to examine the pharmacokinetics of intravenous dalteparin (Fragmin, Pharmacia-Upjohn, Peapack, NJ) and to assess the accuracy of standard coagulation-based monitoring techniques as an estimate of drug concentration with which to guide dosing. Knowledge of the kinetic behavior of low-molecular-weight heparins (LMWHs) and the possible utility of coagulation times for monitoring may aid in the development of safe and effective dosing algorithms for percutaneous coronary interventions. Twenty normal volunteers were treated at 2-week intervals with each of three intravenous dalteparin doses. Measurement of anti-IIa, anti-Xa, activated partial thromboplastin time (aPTT), activated clotting time (ACT), and low-range ACT was performed at baseline and at seven additional time points over 8 hours. The half-life of intravenous dalteparin is 77 minutes with slight dose-related variation. The aPTT, LR-ACT, and standard ACT are prolonged after dalteparin administration with the increase closely correlated to anti-Xa activity (aPTT, r = 0.85; LR-ACT, r = 0.79). Classification of anticoagulation intensity range using aPTT or LR-ACT in comparison to anti-Xa activity (0.5-0.99, 1.0-1.49, 1.5-2, >2) displays a level of agreement (kappa: aPTT = 0.69, LR-ACT = 0.59) that is comparable to values reported for coagulation time guidance of unfractionated heparin administration. Standard coagulation times are sensitive to the anticoagulant effect of dalteparin with a degree of correlation that suggests their utility for estimating drug concentration during high dose therapy. Trials establishing a relationship between monitoring and clinical efficacy, and the risk/reward of different treatment ranges alone or in combination with GPIIb/IIIa inhibitors and clopidogrel, are necessary.

Effects of ximelagatran, the oral form of melagatran, in the treatment of caval vein thrombosis in conscious rats.

The antithrombotic effects of direct (ximelagatran and hirudin) and indirect (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT) treatment model in conscious rats. Thrombus formation was induced in the inferior caval vein by total stasis plus topically applied ferric chloride. After 1-h thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a reference to which all other results were compared. In all other groups, the total occlusion was removed after 1 h but a partial stasis was retained, permitting some blood flow around the thrombus. Groups of animals received subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one of four oral doses of ximelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline (control). After the 3-h treatment, mean thrombus weight in the saline group (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group (27.3 +/- 2.7 mg, see above). Ximelagatran decreased thrombus weight in a dose-dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus weight with the highest ximelagatran dose (11.1 +/- 1.3 mg) was similar to that with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression was much less pronounced (20.2 +/- 1.2 mg), compared with ximelagatran and hirudin, even though it was administered at a dose that yielded a similar activated partial thromboplastin time (APTT) prolongation. In conclusion, the results from this DVT treatment model showed that direct thrombin inhibitors ximelagatran and hirudin exhibited superior antithrombotic properties to low molecular weight heparin (LMWH).

The effects of danaparoid, dalteparin and heparin on tissue factor-induced experimental disseminated intravascular coagulation and bleeding time in the rat.

Danaparoid and heparin, on the basis of anti-activated factor X (anti-FXa) activity, were equipotent in accelerating the rate of interaction of FXa and antithrombin III. In rat tissue factor-induced disseminated intravascular coagulation (DIC) models, an intravenous administration of danaparoid inhibited the decrease in plasma fibrinogen and platelet counts and the increase in serum fibrinogen degradation products. Expressed on the basis of anti-FXa activity, these effects were comparable with those of dalteparin and heparin. In rat mesenteric small artery and vein, less bleeding was observed after intravenous administration of danaparoid than after dalteparin or heparin. Danaparoid did not affect adenosine diphosphate- or collagen-induced platelet aggregation, and showed weaker inhibitory effects on aggregation induced by thrombin, or collagen + thrombin, than did dalteparin or heparin. These findings suggest that danaparoid may be useful for the prevention of DIC and has less tendency to cause bleeding than dalteparin or heparin, probably as a result of its weaker ability to inhibit platelet aggregation.