Rivaroxaban versus nadroparin for thromboprophylaxis following thoracic surgery for lung cancer: A randomized, noninferiority trial.

The benefit of rivaroxaban in thromboprophylaxis after oncologic lung surgery remains unknown. To evaluate the efficacy and safety of rivaroxaban, patients who underwent thoracic surgery for lung cancer were enrolled, and randomly assigned to rivaroxaban or nadroparin groups in a 1:1 ratio; anticoagulants were initiated 12-24 h after surgery and continued until discharge. Four hundred participants were required according to a noninferiority margin of 2%, assuming venous thromboembolism (VTE) occurrence rates of 6.0% and 12.6% for patients in the rivaroxaban and nadroparin groups, respectively. The primary efficacy outcome was any VTE during the treatment and 30-day follow-up periods. The safety outcome was any on-treatment bleeding event. Finally, 403 patients were randomized (intention-to-treat [ITT] population), with 381 included in per-protocol (PP) population. The primary efficacy outcomes occurred in 12.5% (25/200) of the rivaroxaban group and 17.7% (36/203) of the nadroparin group (absolute risk reduction, -5.2%; 95% confidence interval [CI], [-12.2-1.7]), indicating the noninferiority of rivaroxaban in ITT population. Sensitivity analysis was performed in the PP population and yielded similar results, confirming the noninferiority of rivaroxaban. In the safety analysis population, the incidence of any on-treatment bleeding events did not differ significantly between the groups (12.2% for rivaroxaban vs. 7.0% for nadroparin; relative risk [RR], 1.9; 95% CI, [0.9-3.7]; p = .08), including major bleeding (9.7% vs. 6.5%; RR, 1.6 [95% CI, 0.9-3.7]; p = .24), and nonmajor bleeding (2.6% vs. 0.5%; RR, 5.2 [95% CI, 0.6-45.2]; p = .13). Rivaroxaban for thromboprophylaxis after oncologic lung surgery was shown to be noninferior to nadroparin.

Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency.

INTRODUCTION: Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments. AREAS COVERED: We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. EXPERT OPINION: The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50-65% and 75-85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30-60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin.

Bleeding complications of thromboprophylaxis with dabigatran, nadroparin or rivaroxaban for 6 weeks after total knee arthroplasty surgery: a randomised pilot study.

OBJECTIVES: For the non-vitamin-K oral anticoagulants, data on bleeding when used for 42 days as thromboprophylaxis after total knee arthroplasty (TKA) are scarce. This pilot study assessed feasibility of a multicentre randomised clinical trial to evaluate major and clinically relevant non-major bleeding during 42-day use of dabigatran, nadroparin and rivaroxaban after TKA. PATIENTS AND METHODS: In 70 weeks, between July 2012 and November 2013, 198 TKA patients were screened for eligibility in the Martini Hospital (Groningen, the Netherlands). Patients were randomly assigned to dabigatran (n=45), nadroparin (n=45) or rivaroxaban (n=48). The primary outcome was the combined endpoint of major bleeding and clinically relevant non-major bleeding. Secondary endpoints of this study were the occurrence of clinical venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis), compliance, duration of hospital stay, rehospitalisation, adverse events and Knee Injury and Osteoarthritis Outcome Score (KOOS). RESULTS: The primary outcome was observed in 33.3% (95% CI 20.0% to 49.0%), 24.4% (95% CI 12.9% to 39.5%) and 27.1% (95% CI 15.3% to 41.8%) of patients who received dabigatran, nadroparin or rivaroxaban, respectively (p=0.67). Major bleeding was found in two patients who received nadroparin (p=0.21). Clinically relevant non-major bleeding was observed in 33.3% (95% CI 20.0% to 49.0%), 22.2% (95% CI 11.2% to 37.1%) and 27.1% (95% CI 15.3% to 41.8%) for dabigatran, nadroparin and rivaroxaban, respectively (p=0.51). Wound haematoma was the most observed bleeding event. VTE was found in one patient who received dabigatran (p=0.65). The presurgery and postsurgery KOOS qQuestionnaires were available for 32 (71%), 35 (77%) and 35 (73%) patients for dabigatran, nadroparin and rivaroxaban, respectively. KOOS was highly variable, and no significant difference between treatment groups in mean improvement was observed. CONCLUSIONS: A multicentre clinical trial may be feasible. However, investments will be substantial. No differences in major and clinically relevant non-major bleeding events were found between dabigatran, nadroparin and rivaroxaban during 42 days after TKA. KOOS may not be suitable to detect functional loss due to bleeding. TRIAL REGISTRATION NUMBER: NCT01431456.

Comparative Analysis of the Suspected Heparin-Induced Thrombocytopenia Level in Korea.

The primary objective of our study was to evaluate the frequency of suspected heparin-induced thrombocytopenia (HIT) among patients treated with different formulations of heparin and investigate the factors that affect the incidence of HIT. This study is an electronic medical record (EMR)-based large-scale retrospective cohort study conducted from 2009 to 2014 in Korea. After hospitalization, patient platelet count was determined before heparin was prescribed, and all platelet count values obtained during hospitalization were extracted. Suspected HIT was estimated by three 4Ts scores (acute thrombocytopenia, timing onset and other possible causes), which when combined yielded a high probability of HIT. Among 6046 patients enrolled in this study, HIT was suspected in 641 cases (10.6%) and a statistically significant increase in HIT incidence rate was observed for three heparins used (p < 0.001). Dalteparin (HR = 0.55, p = 0.036) and enoxaparin (HR = 0.40, p < 0.001) showed a relatively low HIT incidence rate, compared to unfractionated heparin. Majority of suspected HIT cases (76.9 and 66.7%) occurred in days 8-10 and 5-7 of dalteparin and enoxaparin treatments, respectively. Most of the patients medicated with dalteparin were cancer patients; however, no statistically significant relationship was observed between HIT occurrence and cancer. HIT can cause serious complications, making early diagnosis crucial. Clinical practitioners first prescribing heparin should focus on preventing and detecting complications early by conducting frequent, regular platelet counts before and after heparin administration.

Effects of five treatment regimens on blood loss and blood transfusion in total knee arthroplasty: a preliminary study in China
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OBJECTIVE: Our study is aimed to explore effects of five treatment regimens on blood loss and blood transfusion rate in total knee arthroplasty (TKA) patients. METHODS: 191 TKA patients were divided into the rivaroxaban, nadroparin, and tranexamic acid groups (n = 37 each) as well as into the affected-limb-position and tourniquet group (n = 40 each). A 3-month follow-up after operation was needed for all patients. The total blood loss, hidden blood loss, and dominant blood loss were recorded, and hemoglobin and red blood cell changes, pain and knee swelling degrees, hospital for special surgery (HSS), and American knee society (KSS) knee scores were observed. RESULTS: When compared with the rivaroxaban, nadroparin, and tourniquet groups, TKA patients' dominant blood loss, hidden blood loss, total blood loss, rate and volume of blood transfusion in the tranexamic acid and affected-limb-position groups were significantly decreased. While 7 days after operation, the hemoglobin and red blood cells in the tranexamic acid and affected-limb-position groups were significantly increased. At 1 month and 3 months after operation, when compared with the rivaroxaban, nadroparin, and tourniquet groups, the HSS and KSS scores in the tranexamic acid and affected-limb-position groups were all increased. In comparison with the rivaroxaban, nadroparin, and tourniquet groups, the D-Dimers after operation in the tranexamic acid and affected-limb-position groups were significantly lower. CONCLUSION: These results demonstrated that for TKA patients, the tranexamic acid and affected-limb-position could obviously reduce the blood loss and blood transfusion rate.
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Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538. FINDINGS: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2. INTERPRETATION: Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective. FUNDING: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research.

The safety and efficacy of Heparin and Nadroparin compared to placebo in acute ischemic stroke - pilot study.

AIMS: This study aimed to compare the efficacy and safety of heparin and nadroparin in order to provide an additional therapeutic option for patients with acute ischemic stroke in, whom systemic thrombolysis was excluded, or thrombectomy could not be performed. METHODS: We describe a prospective randomized double-blind placebo-controlled pilot study in acute ischemic stroke. The therapeutic window was between 4.5 and 24 h after the onset of stroke. During the first 24 h of treatment, the patients divided into 3 groups received placebo, heparin or nadroparin (in therapeutic doses). During the following 48 h, each patient received nadroparin in the therapeutic dose. 24 h after start of treatment they began taking 100 mg aspirin daily. The primary safety indicator was incidence of complications such as intracerebral or systemic hemorrhage, or death. Efficacy was primarily monitored by the neurological modified Rankin Scale (mRS) at 90 days. RESULTS: There were no signs of intracerebral or systemic bleeding in the cohort of 87 patients. Two patients died - one (3.7%) in the heparin and one (3.8%) in the placebo group due to causes not connected with the treatment. There was a statistically significant difference in mRS on the 90th day between the heparin and placebo groups (21 (80%) vs 13 (50%), P=0.0350) and between the nadroparin and placebo groups (29 (85%) vs 13 (50%), P=0.0031). CONCLUSION: The results show that the treatment with heparin and nadroparin is safe and effective. TRIAL REGISTRATION: Trial is registered in ClinicalTrials.gov: NCT01862978.

Fatal intrahepatic hemorrhage after nadroparin use for total hip arthroplasty.

Low-molecular-weight heparins have become the predominant choice for deep venous thrombosis prophylaxis and treatment. However, their use may cause bleeding complications. Intrahepatic bleeding is exceptional and only very few cases have been described. The authors present a unique case of fatal intrahepatic hematoma complicating nadroparin use in a 65-year-old woman with a hepatic cyst who was admitted to hospital for unilateral total hip arthroplasty. At autopsy, hemoperitoneum (2,000 ml of blood and clots) was evident. A ruptured sub-capsular hematoma involving the right lobe of the liver was observed. The hemorrhage within the cyst induced by the nadroparin use was likely responsible for the subsequent hepatic hematoma, liver rupture, and death. This case highlights the need for pathologists and surgeons to be aware of the possibility of intrahepatic hematoma in patients who have received low-molecular-weight heparins, undergone major surgery and present postoperative hemodynamic instability, especially in those with preoperative diagnosis of hepatic cyst.

Subcutaneous nadroparin calcium in the treatment of recent onset retinal vein occlusion: a pilot study.

PURPOSE: Optimal management of retinal vein occlusion (RVO) is still a matter of debate. The purpose of this pilot study was to investigate whether nadroparin calcium may play some role in the treatment of recent onset (≤3 weeks' duration) RVO. METHODS: Twenty-four RVO patients were treated with subcutaneous nadroparin calcium (200 I.U./kg/day) for 6 weeks. Best corrected visual acuity (BCVA) and macular thickness in the affected eye were measured at baseline, and after 3 and 6 months. Twenty-four RVO patients treated with oral pentoxifylline, matched for age, gender, RVO type, eye involvement, and BCVA at presentation, randomly selected from the RVO register, were used as controls. RESULTS: Median BCVAs at baseline, month 3, and month 6 were 20/70 (range: 20/1,000-20/20), 20/40 (range: 20/100-20/20), and 20/30 (range: 20/200-20/20) in cases and 20/70 (range: 20/1,000-20/20), 20/60 (range: 20/320-20/25), and 20/60 (range: 20/500-20/20) in controls. Differences between groups were statistically significant at months 3 (P=0.025) and 6 (P=0.024). In the study group, the mean macular thickness was 510±207 µm at baseline, 384±198 µm after 3 months, and 313±170 µm after 6 months. Differences between baseline and months 3 and 6 were statistically significant (P=0.004 and P<0.001). CONCLUSIONS: Results suggest that nadroparin calcium might become a potential candidate for the treatment of RVO. Larger trials are necessary to confirm these preliminary findings.

An unusual adverse effect of nadroparin injections: Calcinosis cutis.

In 1988, Tumiati et al described the first case of calcinosis cutis related to a calcium-containing heparin. Since then, only 18 cases have been reported in the literature; they usually have an altered calcium-phosphate product, an elevated parathyroid hormone (PTH), or both. We report a 33-year-old patient who developed calcinosis cutis at sites of nadroparin injections without any disturbance of calcium-phosphate product, PTH, or vitamin D. The pathogenesis of calcinosis cutis secondary to nadroparin injections remains controversial; Proposed causes included metastatic, dystrophic, iatrogenic, or multifactorial etiologies. This is the first case of multiple nodules of calcinosis cutis without alterations of calcium-phosphate product, PTH, or vitamin D, which supports an iatrogenic mechanism. We also suggest that calcinosis cutis could be more frequent than we thought and is probably an underdiagnosed entity.

Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study.

BACKGROUND: Cancer patients receiving chemotherapy are at increased risk of thrombosis. Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events (TEs) by about 50% in cancer outpatients receiving chemotherapy. The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy. METHODS: Cancer outpatients were randomly assigned to receive subcutaneous injections of nadroparin or placebo. The incidence of symptomatic TEs was assessed according to the type of chemotherapy. Results were reported as risk ratios with associated 95% CI and two-tailed probability values. RESULTS: 769 and 381 patients have been evaluated in the nadroparin and placebo group, respectively. In the absence of thromboprophylaxis, the highest rate of TEs was found in patients receiving gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2%. Thromboprophylaxis reduced TE risk by 68% in patients receiving gemcitabine; with a further decrease to 78% in those receiving a combination of gemcitabine and platinum. CONCLUSIONS: This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Our results also suggest that outpatients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin. CLINICAL TRIAL REGISTRATION NUMBER: NCT 00951574.

Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer.

PURPOSE: Earlier studies showed that low molecular weight heparin significantly prolongs the survival of a wide variety of patients with cancer without venous thromboembolism. This study was designed to confirm these findings in a more homogeneous group of patients with cancer. PATIENTS AND METHODS: In this multicenter, randomized, open-label study, patients with non-small-cell lung cancer (stage IIIB), hormone-refractory prostate cancer, or locally advanced pancreatic cancer were randomly assigned to nadroparin or to no nadroparin in addition to their standard anticancer treatment. In the nadroparin arm, subcutaneous nadroparin was administered for 6 weeks (2 weeks at therapeutic dose, and 4 weeks at half therapeutic dose). The patients were eligible to receive additional cycles of nadroparin (2 weeks at therapeutic dose, and 4 weeks of washout period). Outcomes were overall survival, time to progression, and major bleeding. All study outcomes were adjudicated by an independent, blinded committee. RESULTS: A total of 244 patients were allocated to nadroparin, and 259 were allocated to the control group. A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no-treatment arm (hazard ratio, 0.94; 95% CI, 0.75 to 1.18, adjusted for cancer type). No difference in time to progression was observed. The number of major bleedings was comparable at 4.1% in the nadroparin set and 3.5% in the control set. CONCLUSION: This study did not show a survival benefit of nadroparin in patients with advanced prostate, lung, or pancreatic cancer. Given the ongoing studies in this area and the previous data, the role of low molecular weight heparins in cancer survival remains undefined.

Low allergenic potential with fondaparinux: results of a prospective investigation.

OBJECTIVE: To determine the incidence and causes of skin reactions to the synthetic pentasaccharide fondaparinux. PATIENTS AND METHODS: Patients who received prophylactic/therapeutic subcutaneous fondaparinux treatment for more than 7 days were prospectively examined for cutaneous adverse effects between September 1, 2008, and April 30, 2009. When indicated, other procedures, such as skin biopsy, allergy testing, and clinical/laboratory assessment for thrombosis and heparin-induced thrombocytopenia, were performed. RESULTS: Overall, 231 patients were enrolled. No patient developed typical delayed type IV hypersensitivity (DTH) erythematous skin lesions. However, one female patient experienced abdominal pruritus at sites of injection. Histology revealed a mild lymphohistiocytic infiltrate, confirming a DTH reaction. Heparin-induced thrombocytopenia, as another possible underlying pathomechanism for cutaneous lesions, was ruled out clinically and serologically. Hence, the overall incidence of fondaparinux-induced allergic skin lesions was 0.4% (95% confidence interval, 0.01%-2.4%). No cross-allergies were observed in patients with DTH reaction to heparins. CONCLUSION: Fondaparinux has a low allergenic potential. The incidence of allergic cutaneous DTH reactions is almost 20 times lower compared to that with commonly used heparins. These results, together with the known low prevalence of secondary thrombotic events or heparin-induced thrombocytopenia during fondaparinux therapy, suggest that in selected patients fondaparinux might substantially improve patient care, therapeutic safety, and cost-effectiveness of anticoagulant therapy. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00510432.

Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study.

BACKGROUND: Treatment of isolated calf muscle vein thrombosis (ICMVT) is controversial. There are no data from prospective, controlled studies. Objective of this article was to compare the efficacy and safety of a short-term course of anticoagulation with compression therapy alone. METHODS: We prospectively randomized patients with symptomatic, sonographically proven ICMVT in the soleal and/or gastrocnemial muscle veins in two treatment arms. The first received low-molecular-weight heparin for 10 days at therapeutic dosage (nadroparin 180 anti-activated factor X units once daily) and compression therapy for three months, and the second received compression therapy alone. Primary efficacy endpoint of the study was sonographically proven progression of ICMVT into the deep veins and clinical pulmonary embolism (PE) as confirmed by objective testing. Secondary efficacy and primary safety endpoints were major bleeding, death not due to PE, and complete sonographically proven recanalization of the muscle vein. We assessed transient and permanent risk factors for venous thromboembolism. RESULTS: One-hundred seven patients were finally ruled eligible for evaluation: 89% outpatients, 11% hospitalized patients. In the heparin group (n=54) progression to deep vein thrombosis (DVT) occurred in two patients (3.7%), in the group compression therapy alone (n=53) progression to DVT occurred in two patients (n.s.). No clinical PE and no death occurred. Thrombus recanalization after 3 months was not statistically significant different between the two study groups. No major bleeding occurred. CONCLUSION: The data do not show superiority of a short-term regimen of low-molecular-weight heparin and compression therapy in comparison with compression therapy alone in patients with ICMVT in a rather low-risk population.

Heparin-induced thrombocytopenia associated with pulmonary embolism.

Type II heparin-induced thrombocytopenia (HIT) is a potentially severe adverse effect of heparin treatment triggered by an immune response. Although most cases occur in patients receiving unfractioned heparin, HIT can also arise after low-molecular-weight heparin (LMWH). We report a case of HIT in a postoperative orthopedic 75-year-old woman in treatment with LMWH (nadroparin) complicated by pulmonary embolism and treated successfully with recombinant hirudin. Early recognition and proper treatment are fundamental for the management of this life-threatening disorder.

[Prevention of deep venous thrombosis after knee arthroscopy. Recent advances]. / Recenti acquisizioni sulla tromboprofilassi dopo artroscopia del ginocchio.

In absence of prophylaxis, the incidence of deep vein thrombosis after knee arthroscopy is reported to be as high as 18%. Recommendations for thromboprophylaxis after knee arthroscopy have actually been updated. The results of the largest randomized clinical trial (KANT study) in this setting are reported together with a review of the literature.