Structured benefit-risk assessment for enoxaparin, in the context of its label extension, for the extended treatment of deep vein thrombosis and pulmonary embolism, and prevention of its recurrence in patients with active cancer.

PURPOSE: Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer-associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit-risk profile of enoxaparin with dalteparin and tinzaparin for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. METHODS: A semi-quantitative structured benefit-risk assessment was conducted for the label-extension application of enoxaparin based on the benefit-risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. RESULTS: The key benefits were defined as reduced all-cause mortality and venous thromboembolism (VTE) recurrence (including symptomatic DVT, fatal PE or non-fatal PE); the key risks were major and non-major bleeding of clinical significance, and heparin-induced thrombocytopenia (HIT). Enoxaparin demonstrated comparable effects for the reduction of VTE recurrence and all-cause mortality versus other EEA-approved LMWHs (dalteparin, tinzaparin). There was no evidence of a significant difference between enoxaparin and the comparator groups with regard to incidence of major and non-major bleeding. The data on HIT were too limited to assess the difference between the two groups. CONCLUSIONS: The assessment demonstrated a favourable benefit-risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.

Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study.

BACKGROUND: Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin and standard of care in cancer-associated VTE (CA-VTE). Tinzaparin has the highest molecular weight of all LMWH and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20 mL/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20 mL/min and in CA-VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. AIMS: We aim to confirm the deliverability of tinzaparin in patients with renal insufficiency. METHODS: Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50 mL/min with an indication for anticoagulation. Tinzaparin was given as a subcutaneous injection at 175 units/kg as a single daily dose, rounded to the nearest vial size. Tinzaparin anti-Xa levels were tested at Days 2, 7 and 14 (±1 day) and transition to oral anticoagulants were allowed at clinician discretion. RESULTS: No accumulation of tinzaparin was seen into Day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor) and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and body surface area-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on Day 2, and this effect was lost when patients with CrCl >50 mL/min were excluded. Data from our cohort confirm the deliverability of therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50 mL/min. Bleeding and death outcomes were also comparable to other trials using tinzaparin in CA-VTE. CONCLUSION: For patients with renal insufficiency, tinzaparin represents an attractive alternative anticoagulant with once-daily administration in a range of potential indications.

Tinzaparin-a review of its molecular profile, pharmacology, special properties, and clinical uses.

PURPOSE: Low molecular weight heparins (LMWHs) are a group of heterogenous moieties, long used in the prevention and treatment of thrombosis. They derive from heparin and since they are prepared by different methods of depolymerization, they differ in pharmacokinetic properties and anticoagulant profiles, and thus are not clinically interchangeable. METHODS: In this review we provide an overview of tinzaparin's main characteristics and uses. RESULTS: Tinzaparin which is produced by the enzymatic depolymerization of unfractionated heparin (UFH) can be used for the treatment and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE); it has been also used in special populations such as elders, obese, pregnant women, and patients with renal impairment and/or cancer with favorable outcomes in both safety and efficacy, with a once daily dose regimen. Furthermore, LMWHs are extensively used in clinical practice for both thromboprophylaxis and thrombosis treatment of COVID-19 patients. CONCLUSION: Tinzaparin features support the hypothesis for having a role in immunothrombosis treatment (i.e. in the context of cancer ,COVID-19), interfering not only with coagulation cascade but also exhibiting anti-inflammatory potency.

Can thromboprophylaxis build a link for cancer patients undergoing surgical and/or chemotherapy treatment? The MeTHOS cohort study.

BACKGROUND: Patients with active cancer have a 4-sevenfold increased risk for venous thromboembolism (VTE) especially during systematic anticancer treatment. Simultaneously, surgery is an additional risk factor. METHODS: The Metaxas's Hospital THromboprophylaxis program in Oncological & Surgical Patients (MeTHOS) is a prospective, phase IV, observational, non-interventional cohort study, aiming to record the thromboprophylaxis practice patterns in high-risk active cancer patients undergoing surgical and/or chemotherapy treatment. RESULTS: We are reporting results from 291 ambulatory patients (median age: 67 years, Q1-Q3: 59-73 years, 54.6% males) who received anti-neoplastic treatment and administered thromboprophylaxis. 59.8% had cardiovascular disease (mostly hypertension), 76.6% were reported as having at least one comorbidity, while 27.5% and 15.8% accumulated two and three comorbidities, respectively. 94.9% of the patients were receiving highly thrombogenic agents such as platinum-based agents, 5-FU, immunotherapy, antiangiogenics/anti-VEGF, or erythropoietin. 26.5% of the patients were initially surgically treated. In terms of anticoagulation, all patients were treated with tinzaparin (fixed dose, 10,000 Anti-Xa IU, OD). The median anticoagulation duration was 6.2 months. Six thrombotic events were observed (2.06%, 95% CI: 0.76-4.43%): 5 were DVT, and one PE. With respect to safety, 7 bleeding events occurred (2.6%, 95% CI: 1.0-5.3%); 6 of them were minor. CONCLUSIONS: Thromboprophylaxis with LMWH in patients with active cancer and high thrombotic burden was safe and effective. Intermediate dose of tinzaparin seems to be an appropriate agent for cancer-associated thromboprophylaxis management. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04248348.

Clinical use of low-dose parenteral anticoagulation, incidence of major bleeding and mortality: a multi-centre cohort study using the French national health data system.

PURPOSE: Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates. METHODS: A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models. RESULTS: Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N = 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (≥ 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin. CONCLUSION: Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02886533.

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Thromboembolic and bleeding complications following primary total knee arthroplasty : a Danish nationwide cohort study.

AIMS: The aim of this study is to compare the effectiveness and safety of thromboprophylactic treatments in patients undergoing primary total knee arthroplasty (TKA). METHODS: Using nationwide medical registries, we identified patients with a primary TKA performed in Denmark between 1 January 2013 and 31 December 2018 who received thromboprophylactic treatment. We examined the 90-day risk of venous thromboembolism (VTE), major bleeding, and all-cause mortality following surgery. We used a Cox regression model to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome, pairwise comparing treatment with dalteparin or dabigatran with rivaroxaban as the reference. The HRs were both computed using a multivariable and a propensity score matched analysis. RESULTS: We identified 27,736 primary TKA patients who received thromboprophylactic treatment (rivaroxaban (n = 18,846); dalteparin (n = 5,767); dabigatran (n = 1,443); tinzaparin (n = 1,372); and enoxaparin (n = 308)). In the adjusted multivariable analysis and compared with rivaroxaban, treatment with dalteparin (HR 0.68 (95% CI 0.49 to 0.92)) or dabigatran (HR 0.31 (95% CI 0.13 to 0.70)) was associated with a decreased risk of VTE. No statistically significant differences were observed for major bleeding or all-cause mortality. The propensity score matched analysis yielded similar results. CONCLUSION: Treatment with dalteparin or dabigatran was associated with a decreased 90-day risk of VTE following primary TKA surgery compared with treatment with rivaroxaban. Cite this article: Bone Joint J 2021;103-B(10):1571-1577.

Tinzaparin Safety in Patients With Cancer and Renal Impairment: A Systematic Review.

Low-molecular-weight heparins are approved for primary and secondary venous thromboembolism prevention. Tinzaparin is the low-molecular-weight heparin with the highest average molecular weight. The purpose of this systematic review is to provide an update regarding the safety profile of tinzaparin, prescribed either as a prophylactic or as a therapeutic regimen for venous thromboembolism in special populations, including cancer patients and patients with renal impairment. We identified prospective studies up to August 2020 reporting safety outcomes for cancer patients and patients with renal impairment on tinzaparin regimens. In patients with cancer major bleeding rates fluctuated between 0.8% and 7%. Patients on tinzaparin exhibited significantly lower rates of clinically relevant nonmajor bleeding events in comparison with those on vitamin K antagonists. Bioaccumulation of tinzaparin was not correlated with age, body weight or creatinine clearance. Periodic administration of either prophylactic or therapeutic doses of tinzaparin did not result in bioaccumulation, even in patients with severe renal impairment and creatinine clearance < 20 ml/min. Major bleeding rates for non-cancer patients with renal impairment on prophylactic tinzaparin regimens were 0%. Non-cancer patients with renal impairment on therapeutic tinzaparin regimens exhibited major bleeding in 0 to 3.4% of cases; major bleeding rates were higher for cancer patients with renal impairment on therapeutic tinzaparin regimens (4.3 to 10%). Tinzaparin can be used without dose adjustment in patients with severe renal impairment and creatinine clearance > 20 ml/min. Tinzaparin represents a safe choice for special populations at increased risk for thrombosis and bleeding.

Spontaneous tension pneumothorax and acute pulmonary emboli in a patient with COVID-19 infection.

The COVID-19 pandemic has had a significant impact on the structure and operation of healthcare services worldwide. We highlight a case of a 64-year-old man who presented to the emergency department with acute dyspnoea on a background of a 2-week history of fever, dry cough and shortness of breath. On initial assessment the patient was hypoxic (arterial oxygen saturation (SaO2) of 86% on room air), requiring 10 L/min of oxygen to maintain 98% SaO2 Examination demonstrated left-sided tracheal deviation and absent breath sounds in the right lung field on auscultation. A chest radiograph revealed a large right-sided tension pneumothorax which was treated with needle thoracocentesis and a definitive chest drain. A CT pulmonary angiogram demonstrated segmental left lower lobe acute pulmonary emboli, significant generalised COVID-19 parenchymal features, surgical emphysema and an iatrogenic pneumatocoele. This case emphasises the importance of considering coexisting alternative diagnoses in patients who present with suspected COVID-19.

Treatment of venous thromboembolism with tinzaparin in oncological patients.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. For over a decade, the gold standard of treatment and secondary prevention of cancer-associated thrombosis (CAT) has been represented by low-molecular-weight heparins (LMWHs), which are currently recommended as the first-line treatment for CAT. Among the LMWHs that were more extensively tested in patients with CAT, tinzaparin is a LMWH produced by the enzymatic degradation of porcine-derived unfractionated heparin. The efficacy of tinzaparin in this setting is supported by well-grounded evidence. However, there is a need to discuss the positioning of tinzaparin in the continuously evolving treatment scenario of VTE therapy in cancer patients. In this paper, which was developed by a group of clinicians with wide experience in the treatment of VTE in cancer patients, we discuss the current therapeutic options and the role of tinzaparin for the treatment of CAT.

Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial.

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated.Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg-1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival.In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean±sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II-III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92-1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68-1.30; p=0.70).Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents.

Tinzaparin for the treatment of foetal growth retardation: An open-labelled randomized clinical trial.

OBJECTIVE: Foetal growth retardation (FGR) is a leading cause of perinatal death and long-term harms at survivors. Placental infarction plays a role in FGR, yet, no trials have evaluated whether low molecular weight heparins increase birth weight in ongoing FGR pregnancies. METHODS: An open-labelled randomized trial in Denmark during 2011-2016, including singleton pregnant women with FGR (estimated foetal weight < 2.3 percentile) diagnosed before gestational weeks 32. Participants were randomly assigned using sealed, blinded envelopes 1:1 to tinzaparin (4500 IU daily until 37 gestational weeks) or no tinzaparin. The primary outcomes were the observed birthweight relative to the expected for gestational age and gender, and foetal growth rates in the two trial groups evaluated by an intention to treat analysis. RESULTS: We enrolled 53 women. The mean gestational age was 261 days in the tinzaparin group and 246 days in the no treatment group. The mean birth weight was 2229 g in the tinzaparin group compared to 1968 g in the no treatment group. However, the birth weight relative to the expected from gestational age and gender was only 2.5 percentage points higher in the tinzaparin group [-5.1 to 10.0] (p = 0.51). The foetal growth rate during follow-up was 124 g/week in the tinzaparin group and 119 g/week in the no treatment group, a difference of 5 g/week [-19 to 29] (p = 0.67). Two perinatal deaths both occurred in the no treatment group. CONCLUSION: We found no evidence of a tinzaparin effect on the foetal growth rate or the birth weight after adjustment for gestational age.

Compliance with current VTE prophylaxis guidelines and risk factors linked to complications of VTE prophylaxis in medical inpatients: a prospective cohort study in a Spanish internal medicine department.

OBJECTIVES: To evaluate the degree of compliance with the current guidelines regarding venous thromboembolism (VTE) prophylaxis in medical patients during admission and to identify risk factors linked to complications of VTE prophylaxis. DESIGN: Prospective cohort study. SETTING: The Internal Medicine Department of the University Hospital of Santiago de Compostela (tertiary referral hospital). PARTICIPANTS: A total of 396 hospitalised, elderly patients who did not undergo surgery and had no active or previous oral anticoagulation or low molecular weight heparin (LMWH) treatment (during the previous year) and who received VTE prophylaxis during admission. PRIMARY AND SECONDARY OUTCOME MEASURES: The degree of compliance with the current guidelines was estimated by calculating PADOVA and IMPROVE indexes in all cases. We analysed the development of the following complications: major and minor bleeding, major and minor haematoma and decrease of platelet count. RESULTS: We found that VTE prophylaxis was correctly indicated in 88.4% of patients. We found two (0.5%) cases with major bleeding, 17 (4.3%) with minor bleeding, 30 (7.6%) with decreased platelet count, 29 (7.3%) with major haematoma and 82 (20.7%) with minor haematoma. After multivariate logistic regression analysis, the presence of major haematomas was linked to obesity (OR 4.1; 95% CI 1.8 to 9.2, p=0.001), concomitant antiplatelet treatment (OR 2.7; 95% CI 1.1 to 6.5, p=0.03) and enoxaparin use (OR 3.5; 95% CI 1.1 to 10.9, p=0.029), and the presence of minor haematomas was associated with PADOVA index <4 points (OR 3.1; 95% CI 1.5 to 6.4, p=0.003) and diabetes mellitus (OR 2; 95% CI 1.1 to 3.7, p=0.031). CONCLUSIONS: Complications during VTE prophylaxis in elderly hospitalised medical patients are frequent even with correct application of current guidelines. The main factors linked to haematomas were obesity and concomitant antiplatelet treatment, the presence of which should lead physicians to exercise extreme caution. The use of tinzaparin for VTE prophylaxis in these patients could have a better safety profile.