Drug products: Fragmin, Fragmin®, Fragmin® (med konserveringsmedel)
ATC code: B01AB04
Substances: dalteparin, dalteparin sodium
Dalteparin has been shown to prevent venous thromboembolism similarly in men and women. In acute myocardial infarction one study found that women had more benefit from dalteparin as antithrombotic treatment.
Dalteparin given in the same dose to men and women with unstable coronary syndrome resulted in more bleedings in women. Women also had a higher anti factor Xa activity, i.e. a higher anticoagulative effect, than men.
No studies with a clinically relevant sex analysis regarding the pharmacokinetics or dosing of dalteparin have been found.
Dalteparin is dosed per kilogram body weight and the dosage regimen is thus individual. The maintenance dosage for unstable coronary artery disease is different in men and women depending on the body weight; the dose 5000 IE two times daily is recommended for women <80 kg and men <70 kg, and the dose 7500 IE two times daily is recommended for women >80 kg and men >70 kg .
Unstable coronary artery disease
Subgroup results from the FRISC II trial (1708 men, 749 women)  indicated that men with unstable coronary artery disease and treatment with early invasive revascularization and medical pretreatment with dalteparin sodium plus antianginal medications reduced their risk of death or recurrent myocardial infarction after 3 months more than women . After 6 months, there was no sex difference in risk . However, due to the relatively low frequence of women, this finding needs to be confirmed. Follow-up after 15 years showed that early invasive treatment had a beneficial effect on the composite end point death or myocardial infarction in men, but no effects in women. However, there was no sex difference in the composite end point death or readmission to hospital for ischemic heart disease .
Prevention of venous thromboembolism
A randomized, placebo-controlled, double-blind study (PREVENT), examined dalteparin for prevention of venous thromboembolic events in medically ill patients (1772 men, 1909 women). Dalteparin 5000 IU once daily for two weeks reduced the incidence of the primary endpoint (risk of symptomatic DVT, asymptomatic proximal DVT, non-fatal or fatal PE and/or sudden death) similarly in men and women [5, 6].
Dalteparin as secondary prevention of VTE among cancer patients was investigated in the CLOT trial (328 men, 348 women), a randomized open-label study. Subgroup analyses showed no sex differences in the efficacy of dalteparin compared to an oral anticoagulant (warfarin or acenocoumarol) .
The FRAMI trial (569 men, 207 women), a randomized double-blind placebo-controlled study, reported that dalteparin 150 IU/kg reduced left ventricular thrombus formation in acute anterior myocardial infarction and female sex was associated with a lower risk of developing left ventricular thrombus (OR 0.50, 95%CI 0.26-0.94) .
In the first FRISC trial (464 men, 273 women), dalteparin was given in the same dose to men and women with unstable coronary artery disease. Women had an increased frequency of minor bleedings during the acute phase treatment (5-8 days, 120 IU/kg twice daily) as well as during home treatment period (35-45 days, self-administration 7500 IU/kg once daily). Relative risk ratio women/men was 2.88 during acute phase and 2.36 during home treatment. The bleeding was mainly ecchymoses at the injection site. Women had a higher antifactor Xa activity during the home treatment phase. In spite of that, multiple regression analyses showed that female sex was associated with high antifactor Xa levels during the acute phase as well as a significant association at the end of the home treatment. The relationship between anti-Xa activity and patient’s sex was significant even after adjusting for age, body weight and smoking. Since the distribution of volume of LMWH (Low molecular weight heparins) seems to be equivalent to the plasma compartment, blood volume might be one factor having influence on the sex- differences in anti-Xa activity .
In the PREVENT trial mentioned above, more women had major bleeds while more men had minor bleeds. However, there were no sex difference in the overall incidence of bleeding . No sex-divided data of safety outcomes were reported in other pivotal studies (FRAMI, CLOT) [7, 8].
The half-time of dalteparin is around 4-5 h during the last trimester in pregnant women compared to 2-4 hours in non-pregnant women which needs to be considered when estimating remaining anticoagulant effect . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-01-24
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson