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

2021 ◽  
Vol 27 ◽  
pp. 107602962097959
Author(s):  
I. A. Vathiotis ◽  
N. K. Syrigos ◽  
E. P. Dimakakos
Keyword(s):  
Systematic Review ◽  
Molecular Weight ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Severe Renal Impairment ◽  
Special Populations ◽  
Low Molecular Weight ◽  
Patients With Cancer

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.

scholarly journals Tinzaparin in Cancer and Renal Impairment: A Systematic Review Focusing on Safety

2020 ◽  
Author(s):  
Ioannis Vathiotis ◽  
Nikolaos Syrigos ◽  
Evangelos Dimakakos
Keyword(s):  
Systematic Review ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Severe Renal Impairment ◽  
Vitamin K Antagonists ◽  
Bleeding Events ◽  
Increased Risk ◽  
Therapeutic Doses

Abstract Purpose: Low-molecular-weight heparins are approved for primary and secondary venous thromboembolism prevention. The purpose of this systematic review is to provide an update regarding the safety profile of tinzaparin sodium, prescribed either as a prophylactic or as a therapeutic regimen for VTE in cancer patients and individuals suffering from renal impairment. Method: We identified and studied clinical studies from 2000 until 2020, reporting safety outcomes for cancer patients and individuals with renal impairment receiving either prophylactic or therapeutic doses of tinzaparin. Results: In patients with cancer major bleeding rates fluctuate between 0.8% and 7%; reported major bleeding rates for non-cancer patients with renal impairment on prophylactic tinzaparin regimens were 0%. Non-cancer patients on therapeutic tinzaparin regimens exhibited major bleeding in 0 to 2.3% of cases; major bleeding rates were higher for cancer patients with renal impairment receiving therapeutic doses of tinzaparin (4.3 to 10%). Patients on tinzaparin exhibit significantly lower rates of clinically relevant nonmajor bleeding events in comparison with those on vitamin K antagonists. Bioaccumulation of tinzaparin is not correlated with age, body weight or creatinine clearance. Periodic administration of either prophylactic or therapeutic doses of tinzaparin does not result in bioaccumulation, even in patients with severe renal impairment and creatinine clearance < 20 ml/min. Conclusion: Tinzaparin is safe and can be used without dose adjustment in patients with severe renal impairment and creatinine clearance > 20 ml/min. Tinzaparin represents a thoroughly studied and safe choice for special populations at increased risk for thrombosis and bleeding.

scholarly journals Tinzaparin in Pregnancy, Cancer and Renal Impairment: A Systematic Review Focusing on Safety

2020 ◽  
Author(s):  
Ioannis Vathiotis ◽  
Nikolaos Syrigos ◽  
Evangelos Dimakakos
Keyword(s):  
Molecular Weight ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Pregnant Women ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Dose Adjustment ◽  
Low Molecular Weight ◽  
Bleeding Events ◽  
Major Bleeding Events

Abstract Background: Low-molecular-weight heparins are approved for primary and secondary venous thromboembolism prevention. Tinzaparin (Innohep®) is the low-molecular-weight heparin with the highest average molecular weight. The purpose of this study is to provide an update regarding the safety profile of tinzaparin sodium, prescribed either as a prophylactic or as a therapeutic regimen for VTE, in pregnant women, cancer patients and individuals suffering from renal impairment. Methods: We identified clinical trials reporting safety outcomes for pregnant women, cancer patients and individuals with renal impairment receiving either prophylactic or therapeutic doses of tinzaparin. We extracted predefined, clinically relevant outcomes of patients on tinzaparin.Results: For pregnant women on tinzaparin bleeding rates ranged from 9.7% to 10.3%; reported rates of major bleeding events, allergic reactions and thrombocytopenia were low. No maternal deaths or neonatal hemorrhages were recorded. Prophylactic administration of tinzaparin also showed promising results in pregnant women with recurrent unexpected pregnancy loss. In patients with cancer bleeding rates fluctuated between 0.8% and 27%; there was a trend showing that patients on tinzaparin exhibited fewer bleeding events than those on vitamin K antagonists. Bioaccumulation of tinzaparin was not correlated with age, body weight or creatinine clearance. Therapeutic administration of tinzaparin did not produce significant increase in the rates of clinically relevant or major bleeding events in patients with renal impairment. Periodic administration of tinzaparin did not result in bioaccumulation and tinzaparin is safe and can be used without dose adjustment in patients with severe renal impairment and creatinine clearance < 20 ml/min.Conclusions: Tinzaparin represents a thoroughly studied and safe choice for special populations that are at increased risk for both thrombosis and bleeding. Tinzaparin is safe for pregnant women. Current literature supports the use of tinzaparin without dose adjustment in patients with renal impairment and creatinine clearance < 20ml/min.

Low-Molecular-Weight Heparin in Cancer Patients: Overview and Indications

2019 ◽  
Vol 39 (01) ◽  
pp. 067-075 ◽  
Author(s):  
Minna Voigtlaender ◽  
Florian Langer
Keyword(s):  
Molecular Weight ◽  
Cancer Patients ◽  
Anticancer Agents ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Low Molecular Weight ◽  
Vte Prophylaxis ◽  
Patients With Cancer ◽  
Increased Risk

AbstractAlthough venous thromboembolism (VTE) is a well-known cause of death in patients with cancer, both its treatment and prevention remain a challenge in daily practice. Direct oral anticoagulants have emerged as safe and efficacious alternatives to vitamin K antagonists in the general population, and recent clinical trials also support their use in select patients with cancer-associated VTE. Despite this, low-molecular-weight heparins (LMWHs), a comparatively ancient class of antithrombotic drugs, remain the anticoagulants of choice in many indications relevant to modern haematology and oncology. In addition to the treatment of established VTE, these indications include VTE prophylaxis in surgical or acutely ill, hospitalized medical cancer patients as well as the prevention of VTE in high-risk patients undergoing ambulatory chemotherapy. In a constantly changing landscape of approved anticancer agents, this review article summarizes pivotal clinical trial data and guideline recommendations regarding the use of LMWH in haematological and oncological patients, who constitute a highly vulnerable patient population due to their increased risk for both bleeding and VTE recurrence.

No Accumulation of Peak Anti-Xa Activity of Tinzaparin in Elderly Patients with Moderate to Severe Renal Impairment: A Substudy of IRIS Clinical Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 172-172 ◽  
Author(s):  
Virginie Siguret ◽  
Alain Leizorovicz ◽  
Eric Pautas ◽  
Isabelle Gouin-Thibault
Keyword(s):  
Infectious Disease ◽  
Clinical Trial ◽  
Molecular Weight ◽  
Renal Impairment ◽  
Elderly Patients ◽  
Creatinine Clearance ◽  
Severe Renal Impairment ◽  
Renal Elimination ◽  
Significant Difference ◽  
The Mean

Abstract Abstract 172 The “Innohep® in Renal Insufficiency Study” (IRIS) was an international, multicentre, open, randomized, parallel group clinical trial with a primary objective to compare the safety of tinzaparin and unfractionated heparin in terms of clinically relevant bleeding (CRB) in elderly patients with impaired renal function for initial treatment of acute deep vein thrombosis. In the elderly, concerns have been raised about the risk of an accumulation effect and/or overdose due to the renal elimination of low molecular weight heparins (LMWH). In a subset of centres participating in the IRIS study, we conducted a substudy in order to assess whether there was an accumulation of anti-Xa activity and whether there was any relationship between anti-Xa activity and age, weight, creatinine clearance or clinical outcomes in patients treated with tinzaparin (175 IU/kg/24h) for venous thromboembolism. Plasma anti-Xa activity was to be analysed at peak level (4–6 hours after injection) on Day 2 or Day 3 and on Day 5 or at visit S (VS: day of visit at end of SC treatment) using a chromogenic assay (Rotachrom® heparin, Diagnostica Stago®). Of the complete IRIS study population who received tinzaparin (n=268), data from 87 patients (32%) were analysed. The patient characteristics (mean age 83±5 years [75–99 years], mean creatinine clearance (Cockcroft-Gault) 40.8 mL/min (SD 11.7, range 14–59) were consistent with those of the overall population of IRIS study. Of note, 24.1% had severe renal impairment (creatinine clearance < 30 mL/min). The mean peak anti-Xa activities, which were 0.86 (SD 0.34) and 0.87 (SD 0.31) IU/mL on Day2/3 and Day5/VS, respectively, were found close to the mean 0.85 IU/mL reported in the literature in patients receiving tinzaparin at therapeutic dose. There was no correlation between the anti-Xa activity and age, weight, or creatinine clearance. There was no significant difference in the anti-Xa levels between patients with, versus those without, severe renal impairment. The mean accumulation ratio (defined as anti-Xa activity on Day5/VS divided by the anti-Xa activity on Day2/3) was 1.06 (SD 0.30, 90% CI:1.01–1.11): as the 90% CI of the accumulation did not exceed the pre-defined upper limit of 1.25, no significant accumulation was detected. The mean anti-Xa activity did not differ significantly between the 8 patients experiencing a CRB during tinzaparin treatment and the 79 who did not experience a CRB during tinzaparin treatment. Among the 8 patients who had a CRB, one had an anti-Xa activity > 2.0 IU/mL (considered above therapeutic level) whereas the seven others had anti-Xa < 1.5 IU/mL. Interestingly, we found that the mean anti-Xa activities were significantly lower in the 12 patients with infectious disease at baseline compared to the patients without infectious disease: 0.66 (SD 0.18) vs 0.8 (SD 0.35) IU/mL on Day2/3, p=0.007; 0.62 (SD 0.23) vs 0.91 (SD 0.30) IU/mL on Day5/VS, p=0.002). These numbers are small but may require further investigation. There was no statistically significant difference in anti-Xa levels when comparing patients with versus those without ongoing malignancy. In conclusion, an IRIS substudy demonstrated no accumulation of anti-Xa activity in elderly patients with moderate to severe renal impairment receiving unadjusted recommended full dose of tinzaparin and confirms previous pharmacokinetic studies in similar populations. The high proportion of higher molecular weight moieties in tinzaparin may account for reduced dependence on renal elimination of the anti-Xa activity seen in elderly patients with renal impairment. Disclosures: Siguret: Leo-Pharma: this work was supported by a grant from Leo-Pharma. Leizorovicz:GSK: Consultancy. Gouin-Thibault:Leo-Pharma: this work was supported by a grant from Leo-Pharma.

Efficacy and safety of direct oral anticoagulants vs. low molecular weight heparin for cancer-related venous thromboembolism: a meta-analysis of randomized trials

2020 ◽  
Author(s):  
Ayman Elbadawi ◽  
Mina Shnoda ◽  
Karim Mahmoud ◽  
Islam Y Elgendy
Keyword(s):  
Molecular Weight ◽  
Major Bleeding ◽  
Lower Incidence ◽  
Low Molecular Weight Heparin ◽  
Randomized Trials ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Low Molecular Weight ◽  
Efficacy And Safety ◽  
Patients With Cancer

Abstract Aims To examine the efficacy and safety of direct oral anticoagulants (DOACs) vs. low molecular weight heparin (LMWH) in patients with cancer-related venous thromboembolism (VTE). Methods and results An electronic search of the MEDLINE, SCOPUS, and Cochrane databases without language restrictions was performed through April 2020 for randomized controlled trials that compared the outcomes with DOACs vs. LMWH among patients with cancer-related VTE. Summary estimates were reported using random effects model. The main efficacy outcome was VTE recurrence, while the main safety outcome was major bleeding . The final analysis included four randomized trials with a total of 2907 patients. The weighted mean follow-up was 6.1 months. Compared with LMWH, DOACs were associated with lower incidence of VTE recurrence [5.7% vs. 9.1%, risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44–0.87; P = 0.01], driven by lower incidence of deep venous thrombosis (RR 0.60, 95% CI 0.39–0.93; P = 0.02). There was no difference in the incidence of major bleeding between DOACs and LMWH (4.8% vs. 3.6%, RR 1.33; 95% CI 0.84–2.11; P = 0.23). The incidence of all-cause mortality was similar (RR 0.99; 95% CI 0.84–1.16; P = 0.91). Subgroup analysis suggested no differences according to the type of DOAC regarding recurrent VTE or major bleeding (Pinteraction = 0.53 and Pinteraction = 0.11, respectively). Conclusion Among patients with cancer-related VTE, DOACs were associated with lower incidence of VTE recurrence and no difference in the incidence of major bleeding compared with LMWH. Future studies examining the subset of cancer patients who drive the most benefit are encouraged.

scholarly journals Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D)

2018 ◽  
Vol 36 (20) ◽  
pp. 2017-2023 ◽  
Author(s):  
Annie M. Young ◽  
Andrea Marshall ◽  
Jenny Thirlwall ◽  
Oliver Chapman ◽  
Anand Lokare ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thromboembolism ◽  
Recurrence Rate ◽  
Major Bleeding ◽  
Low Molecular Weight Heparin ◽  
Pilot Trial ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Factor Xa Inhibitor ◽  
Patients With Cancer

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

scholarly journals Intermediate Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis

2019 ◽  
Vol 45 (08) ◽  
pp. 810-824 ◽  
Author(s):  
Ruben J. Eck ◽  
Wouter Bult ◽  
Jørn Wetterslev ◽  
Reinold O.B. Gans ◽  
Karina Meijer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Molecular Weight ◽  
Major Bleeding ◽  
Low Molecular Weight Heparin ◽  
Risk Of Bias ◽  
Sensitivity Analyses ◽  
Thrombosis Prophylaxis ◽  
Low Molecular Weight ◽  
All Cause Mortality ◽  
Intermediate Dose

AbstractDifferent doses of low-molecular-weight heparin (LMWH) are registered and used for thrombosis prophylaxis. We assessed benefits and harms of thrombosis prophylaxis with a predefined intermediate-dose LMWH compared with placebo or no treatment in patients at risk of venous thromboembolism (VTE). We performed a systematic review with meta-analyses and trial sequential analyses (TSA) following The Cochrane Handbook for Systematic Reviews of Interventions. Medline, Cochrane CENTRAL, Web of Science, and Embase were searched up to December 2018. Trials were evaluated for risk of bias and quality of evidence was assessed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seventy randomized trials with 34,046 patients were included. Eighteen (26%) had overall low risk of bias. There was a small statistically significant effect of LMWH on all-cause mortality (risk ratio [RR]: 0.96; TSA-adjusted confidence interval [TSA-adjusted CI]: 0.94–0.98) which disappeared in sensitivity analyses excluding ambulatory cancer patients (RR: 0.99; TSA-adjusted CI: 0.84–1.16). There was moderate-quality evidence for a statistically significant beneficial effect on symptomatic VTE (odds ratio [OR]: 0.59; TSA-adjusted CI: 0.53–0.67; number needed to treat [NNT]: 76; 95% CI: 60–106) and a statistically significant harmful effect on major bleeding (Peto OR: 1.66; TSA-adjusted CI: 1.31–2.10; number needed to harm [NNH]: 212; 95% CI: 142–393). There were no significant intervention effects on serious adverse events. The use of intermediate-dose LMWH for thrombosis prophylaxis compared with placebo or no treatment was associated with a small statistically significant reduction of all-cause mortality that disappeared in sensitivity analyses excluding trials that evaluated LMWH for anticancer treatment. Intermediate-dose LMWH provides benefits in terms of VTE prevention while it increases major bleeding.

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