Major bleeding risks of different low‐molecular‐weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis

Abstract

Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Prevalence of Hemorrhagic Complications in Hospitalized Patients with Pulmonary Embolism

“…Fondaparinux was only related to minor episodes of hemorrhage. According to studies that have compared it with enoxaparin, the percentage of major hemorrhage in 9 days is much lower when fondaparinux is used rather than enoxaparin [38]. On the other hand, we found that nadroparin related to 83.3% of the major events.…”

“…On the other hand, we found that nadroparin related to 83.3% of the major events. Generally, it has been reported that absolute major bleeding rates are low for all LMWH agents [38]. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with a 1.77 times greater bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials [38,39].…”

“…In the present study, 4.1% were receiving DOACs, and they underwent one major and one minor hemorrhagic episode. Multiple clinical studies support the safer bleeding profile of DOACs over Vitamin K antagonists [38]. However, it has been supported that DOACs at standard dose, except apixaban, had a higher risk of major gastrointestinal bleeding compared to warfarin.…”

Prevalence of Hemorrhagic Complications in Hospitalized Patients with Pulmonary Embolism

“…Fondaparinux was only related to minor episodes of hemorrhage. According to studies that have compared it with enoxaparin, the percentage of major hemorrhage in 9 days is much lower when fondaparinux is used rather than enoxaparin [38]. On the other hand, we found that nadroparin related to 83.3% of the major events.…”

“…On the other hand, we found that nadroparin related to 83.3% of the major events. Generally, it has been reported that absolute major bleeding rates are low for all LMWH agents [38]. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with a 1.77 times greater bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials [38,39].…”

“…In the present study, 4.1% were receiving DOACs, and they underwent one major and one minor hemorrhagic episode. Multiple clinical studies support the safer bleeding profile of DOACs over Vitamin K antagonists [38]. However, it has been supported that DOACs at standard dose, except apixaban, had a higher risk of major gastrointestinal bleeding compared to warfarin.…”

Acquired Hemophilia A Masquerading as Bleeding on Anticoagulation: A Case Report Including Key Laboratory Considerations

“…In retrospect, the initial prolonged aPTT warranted further evaluation which could have prevented her multiple admissions, transfusion of 15 units of packed red blood cells, and the diagnostic delay of about four months. Advanced age is an important risk factor for anticoagulant-associated bleeding [ 5 ]; however, the overall rate of LMWH-related major bleeding is rare and estimated at 2.5 of every 1,000 patients [ 6 ]. The patient was started on a therapeutic LMWH with dalteparin at 200 U/kg, which exceeded the recommended maximum dose of 18,000 U/day, but therapeutic LMWH dosing based on body weight is recommended and has not been shown to increase the risk of bleeding significantly [ 7 ].…”

Alternative physical treatments for deep venous thrombosis prophylaxis in surgical patients: a systematic review

“…Early mobilisation may not be possible for patients unable to transfer to a chair, or weightbear as a result of their condition. Although LMWH has a more predictable effect than unfractionated heparin, it can still lead to an increased risk of surgical site bleeding [28] and is contraindicated in patients at high risk of bleeding [29]. Similarly, graduated compression stockings cannot always be used following recent surgery to the lower extremity, limiting their applicability following foot and ankle surgery and lower limb reconstruction.…”

Prevalence of Hemorrhagic Complications in Hospitalized Patients with Pulmonary Embolism

“…Fondaparinux was only related to minor episodes of hemorrhage. According to studies that have compared it with enoxaparin, the percentage of major hemorrhage in 9 days is much lower when fondaparinux is used rather than enoxaparin [38]. On the other hand, we found that nadroparin related to 83.3% of the major events.…”

“…On the other hand, we found that nadroparin related to 83.3% of the major events. Generally, it has been reported that absolute major bleeding rates are low for all LMWH agents [38]. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with a 1.77 times greater bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials [38,39].…”

“…In the present study, 4.1% were receiving DOACs, and they underwent one major and one minor hemorrhagic episode. Multiple clinical studies support the safer bleeding profile of DOACs over Vitamin K antagonists [38]. However, it has been supported that DOACs at standard dose, except apixaban, had a higher risk of major gastrointestinal bleeding compared to warfarin.…”

Acquired Hemophilia A Masquerading as Bleeding on Anticoagulation: A Case Report Including Key Laboratory Considerations

“…In retrospect, the initial prolonged aPTT warranted further evaluation which could have prevented her multiple admissions, transfusion of 15 units of packed red blood cells, and the diagnostic delay of about four months. Advanced age is an important risk factor for anticoagulant-associated bleeding [ 5 ]; however, the overall rate of LMWH-related major bleeding is rare and estimated at 2.5 of every 1,000 patients [ 6 ]. The patient was started on a therapeutic LMWH with dalteparin at 200 U/kg, which exceeded the recommended maximum dose of 18,000 U/day, but therapeutic LMWH dosing based on body weight is recommended and has not been shown to increase the risk of bleeding significantly [ 7 ].…”

Alternative physical treatments for deep venous thrombosis prophylaxis in surgical patients: a systematic review

“…Early mobilisation may not be possible for patients unable to transfer to a chair, or weightbear as a result of their condition. Although LMWH has a more predictable effect than unfractionated heparin, it can still lead to an increased risk of surgical site bleeding [28] and is contraindicated in patients at high risk of bleeding [29]. Similarly, graduated compression stockings cannot always be used following recent surgery to the lower extremity, limiting their applicability following foot and ankle surgery and lower limb reconstruction.…”

Prevalence of Hemorrhagic Complications in Hospitalized Patients with Pulmonary Embolism

“…Fondaparinux was only related to minor episodes of hemorrhage. According to studies that have compared it with enoxaparin, the percentage of major hemorrhage in 9 days is much lower when fondaparinux is used rather than enoxaparin [38]. On the other hand, we found that nadroparin related to 83.3% of the major events.…”

“…On the other hand, we found that nadroparin related to 83.3% of the major events. Generally, it has been reported that absolute major bleeding rates are low for all LMWH agents [38]. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with a 1.77 times greater bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials [38,39].…”

“…In the present study, 4.1% were receiving DOACs, and they underwent one major and one minor hemorrhagic episode. Multiple clinical studies support the safer bleeding profile of DOACs over Vitamin K antagonists [38]. However, it has been supported that DOACs at standard dose, except apixaban, had a higher risk of major gastrointestinal bleeding compared to warfarin.…”

Acquired Hemophilia A Masquerading as Bleeding on Anticoagulation: A Case Report Including Key Laboratory Considerations

“…In retrospect, the initial prolonged aPTT warranted further evaluation which could have prevented her multiple admissions, transfusion of 15 units of packed red blood cells, and the diagnostic delay of about four months. Advanced age is an important risk factor for anticoagulant-associated bleeding [ 5 ]; however, the overall rate of LMWH-related major bleeding is rare and estimated at 2.5 of every 1,000 patients [ 6 ]. The patient was started on a therapeutic LMWH with dalteparin at 200 U/kg, which exceeded the recommended maximum dose of 18,000 U/day, but therapeutic LMWH dosing based on body weight is recommended and has not been shown to increase the risk of bleeding significantly [ 7 ].…”

Alternative physical treatments for deep venous thrombosis prophylaxis in surgical patients: a systematic review

“…Early mobilisation may not be possible for patients unable to transfer to a chair, or weightbear as a result of their condition. Although LMWH has a more predictable effect than unfractionated heparin, it can still lead to an increased risk of surgical site bleeding [28] and is contraindicated in patients at high risk of bleeding [29]. Similarly, graduated compression stockings cannot always be used following recent surgery to the lower extremity, limiting their applicability following foot and ankle surgery and lower limb reconstruction.…”