Randomized Trial of the Effect of the Low Molecular Weight Heparin Nadroparin on Survival in Patients With Cancer

2011 ◽  
Vol 29 (15) ◽  
pp. 2071-2076 ◽  
Author(s):  
Frederiek F. van Doormaal ◽  
Marcello Di Nisio ◽  
Hans-Martin Otten ◽  
Dick J. Richel ◽  
Martin Prins ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Weight ◽  
Therapeutic Dose ◽  
Low Molecular Weight Heparin ◽  
Locally Advanced ◽  
Control Group ◽  
Low Molecular Weight ◽  
Cancer Type ◽  
Time To Progression ◽  
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.

Systemic Thrombin Generation and Activity Resistant to Low Molecular Weight Heparin Administered Prior to Streptokinase in Patients with Acute Myocardial Infarction

1997 ◽  
Vol 77 (01) ◽  
pp. 057-061 ◽  
Author(s):  
Dennis W T Nilsen ◽  
Lasse Gøransson ◽  
Alf-Inge Larsen ◽  
Øyvind Hetland ◽  
Peter Kierulf
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Molecular Weight ◽  
Body Weight ◽  
Low Molecular Weight Heparin ◽  
Troponin T ◽  
Bleeding Complications ◽  
Control Group ◽  
Low Molecular Weight ◽  
Creatine Kinase Mb

SummaryOne hundred patients were included in a randomized open trial to assess the systemic factor Xa (FXa) and thrombin inhibitory effect as well as the safety profile of low molecular weight heparin (LMWH) given subcutaneously in conjunction with streptokinase (SK) in patients with acute myocardial infarction (MI). The treatment was initiated prior to SK, followed by repeated injections every 12 h for 7 days, using a dose of 150 anti-Xa units per kg body weight. The control group received unfractionated heparin (UFH) 12,500 IU subcutaneously every 12 h for 7 days, initiated 4 h after start of SK infusion. All patients received acetylsalicylic acid (ASA) initiated prior to SK.Serial blood samples were collected prior to and during the first 24 h after initiation of SK infusion for determination of prothrombin fragment 1+2 (Fl+2), thrombin-antithrombin III (TAT) complexes, fibrinopeptide A (FPA) and cardiac enzymes. Bleeding complications and adverse events were carefully accounted for.Infarct characteristics, as judged by creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT), were similar in both groups of patients.A comparable transient increase in Fl+2, TAT and FPA was noted irrespective of heparin regimen. Increased anti-Xa activity in patients given LMWH prior to thrombolytic treatment had no impact on indices of systemic thrombin activation.The incidence of major bleedings was significantly higher in patients receiving LMWH as compared to patients receiving UFH. However, the occurrence of bleedings was modified after reduction of the initial LMWH dose to 100 anti-Xa units per kg body weight.In conclusion, systemic FXa- and thrombin activity following SK-infusion in patients with acute MI was uninfluenced by conjunctive LMWH treatment.

Pharmacodynamics and Tolerance of Two Nadroparin Formulations (10,250 and 20,500 Anti Xa IU·ml-1) Delivered for 10 Days at Therapeutic Dose

1998 ◽  
Vol 79 (02) ◽  
pp. 338-341 ◽  
Author(s):  
C. Navarro ◽  
J. P. Cambus ◽  
H. Caplain ◽  
P. d’Azemar ◽  
J. Necciari ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thromboembolism ◽  
Healthy Volunteers ◽  
Total Dose ◽  
Therapeutic Dose ◽  
Low Molecular Weight Heparin ◽  
Dose Effect ◽  
Low Molecular Weight ◽  
High Dose ◽  
Circadian Effect

SummaryVenous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i. d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU·ml-1 respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU·kg-1 b.i. d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU·kg-1 o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC0-12 h plus AUC12-24 h (treatment A) and the AUC0-24 h (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC0-12 h were slightly but significantly lower than the AUC12-24 h suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 ± 0.25), in relation with the anti-IIa activity (0.3 ± 0.1 IU·ml–1).

The Use of Low Molecular Weight Heparins for Post-Surgical Deep Vein Thrombosis Prevention in Orthopaedic Patients

1988 ◽  
Vol 16 (5) ◽  
pp. 359-366 ◽  
Author(s):  
E. Chiapuzzo ◽  
G. B. Orengo ◽  
G. Ottria ◽  
A. Chiapuzzo ◽  
E. Palazzini ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Deep Vein Thrombosis ◽  
Low Molecular Weight Heparin ◽  
Control Group ◽  
Low Molecular Weight ◽  
Factor X ◽  
Vein Thrombosis ◽  
Orthopaedic Patients ◽  
Antithrombotic Efficacy ◽  
Deep Vein

The prophylactic antithrombotic efficacy of a low molecular weight heparin was compared with a traditional unfractionated calcium heparin after orthopaedic surgery in 140 patients. Deep vein thromboses were detected in legs either by Doppler sonography or [125I]fibrinogen uptake tests in five (7.1%) and seven (10%) patients, respectively. The capacity of both drugs to prevent deep vein thrombosis was demonstrated. Compared with the control group, those who used low molecular weight heparin showed a significant increase of activated factor X inhibition and smaller increases in activated partial thromboplastin times. Tolerability of both drugs was good, with a low incidence of local side-effects.

Use of Therapeutic Dose Low Molecular Weight Heparin in Patients with Renal Insufficiency: Analysis of Anti-Xa Levels and Creatinine Clearance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 884-884
Author(s):  
Wendy Lim ◽  
Manasa Sridhara ◽  
Luqi Wang ◽  
Krystyna Kinnon ◽  
James Douketis ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Therapeutic Dose ◽  
Low Molecular Weight Heparin ◽  
Dose Adjustment ◽  
Low Molecular Weight ◽  
Recurrent Vte ◽  
Dependent Patient

Abstract Low molecular weight heparin (LMWH) is predominantly eliminated by the kidneys. In patients with severe renal impairment, use of therapeutic dose LMWH may be associated with accumulation and a resultant bleeding risk. Tinzaparin may be less dependent on renal clearance due to its higher molecular mass and greater negative charge compared to other LMWHs. The objective of this prospective cohort study was to serially measure the anti-Xa anticoagulant effect of therapeutic dose tinzaparin over 5–7 days, used for the initial treatment of venous thromboembolism (VTE) in patients with varying degrees of renal insufficiency. We present the anti-Xa results from the first 78 patients enrolled in the study, correlated with renal function. In this study, consecutive in- and outpatients with objectively confirmed VTE requiring anticoagulation were enrolled and stratified into 4 groups based on the calculated Cockcroft-Gault creatinine clearance (CrCl): > 60 mL/min, 30–60 mL/min, ≤ 30 mL/min and hemodialysis-dependent. Tinzaparin 175 IU/kg was administered subcutaneously once daily for 5–7 days or until the INR ≥ 2.0 with warfarin therapy. Trough anti-Xa levels were measured prior to the 3rd, 5th and/or 7th tinzaparin doses. Patients with anti-Xa level > 0.5 IU/mL received tinzaparin dose adjustment using a standardized nomogram. Bleeding and recurrent VTE events were recorded. The relationship between anti-Xa levels and CrCl is shown in Figure 1. Based on our predefined anti-Xa threshold of 0.5 IU/mL, 5 of 78 patients (6.4%) required dose adjustment; 1 hemodialysis dependent patient, 2 patients with CrCl < 30 mL/min, 1 patient each with CrCl 30–60 and > 60 mL/min, respectively. None of these patients developed bleeding or recurrent VTE. Among all 78 patients, 1 hemodialysis-dependent patient developed a hematoma following a traumatic line insertion, and no patients developed recurrent VTE. In conclusion, in a cohort of 78 patients with differing degrees of renal function including patients requiring hemodialysis, use of therapeutic-dose tinzaparin for the initial treatment of VTE resulted in accumulation (defined by trough anti-Xa > 0.5 IU/mL) in 6% of patients. There appears to be a weak inverse relationship between renal function and trough anti-Xa levels, but does not result in clinically significant accumulation when tinzaparin is used for up to 7 days. Further evaluation of tinzaparin in patients with severe renal insufficiency is required. Figure Figure

Low Molecular Weight Heparin in Patients with Cancer: A New Option

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4058-4058
Author(s):  
Giorgio Corinaldesi ◽  
Christian Corinaldesi
Keyword(s):  
Molecular Weight ◽  
Cancer Biology ◽  
Low Molecular Weight Heparin ◽  
Low Molecular Weight ◽  
Minor Bleeding ◽  
Vein Thrombosis ◽  
Patients With Cancer ◽  
Cancer Breast ◽  
Metastatic Activity ◽  
Deep Vein

Abstract The use of heparin for venous thromboembolism, upper extremity deep vein thrombosis (DVT), septic thrombophlebitis, loss of central venous device access in patients with cancer is a standard practice; a new clinical evidence suggest that low molecular weight heparin (LMWHs) may prolong survival in patients with cancer and may have anti-neoplastic effects and anti-metastatic activity. We evaluated 74 patients with cancer (38 patients were allocated to enoxaparin 6000UI subcutaneously once a day, and 36 patients were allocated to placebo), the mean duration of follow-up was 12 months, platelet count were performed before the treatment, and once a month; in the event of thrombocytopenia < 50.000/ml or abnormal bleeding the treatment was stopped. The primary end points were overall survival, and metastasis progression. TAB:A Enoxaparin (n.38) Placebo (n.36) Age-years (range) 46–68 48–66 Sex (male/female) 20/18 20/16 Metastasis disease     a) before 10 12     b) end-therapy 12 18 Type of cancer     Breast cancer 8 8     Endometrial cancer 6 5     Gastric or esophageal 4/2 3/1     Colorectal cancer 6/2 8/2     Prostatic cancer 6 7     Urothelial 2 1     Lung 2 1 Death 3 8     Major bleeding 1 0     Minor bleeding 4 4     Allergic reaction 0 0     VTE 6 0 Concomitant anti-neoplastic therapy     Chemotherapy 26 26     Radiotherapy 2 1     Combined 4 3         Hormonal 6 6 These data show that LMWHs reduce or attenuate metastasis at 12 month by 11.4%, and death by 8.8%, with a significant increase of median survival. Heparin have show to have direct antigrowth, antiangiogenesis, and antimetastatic effects, LMWHs minimize angiogenesis with the inhibition of VEGF and b-FGF, inhibit the adhesion of cancer cells to endothelium and the interaction mediated by tumor cells surface mucins and selectin, and they interfere with cancer biology; we can speculate that the binding of tumor growth to heparin have a crucial role in the modulation of activity of the high affinity receptors, it promotes receptors dimerization and activation, inhibits P and L-selectins and chemokine action (IL-8, Mip-1), blocks MMP, serin-protease and heparanase, decreases over-expression of TF and PAF, induces and increases apoptosis.

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