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Warfarin

Classification: A

Drug products: Coumadin, Marevan Uten farge, Waran vita, Waran®, Warfarin AB Unimedic, Warfarin Nycomed, Warfarin Orion

ATC code: B01AA03

Substances: warfarin, warfarin sodium

Summary

Warfarin has been shown to reduce the risk of thromboembolism as effectively in men as in women regardless of age. Some studies have emphasized the potentially greater advantage from anticoagulation in women with atrial fibrillation as the risk of ischemic stroke is higher in this group.

Studies show conflicting evidence regarding sex-differences in the risk of bleeding as an adverse effect of warfarin.

It should be noted that warfarin has potential teratogenic effects. For Swedish readers, please consult
Janusmed Drugs and Birth Defects
.
 

Additional information

Pharmacokinetics and dosing

No studies with a clinically relevant sex analysis regarding pharmacokinetics of warfarin have been found.

A cohort study (2 655 men, 1 961 women) found that warfarin dose was inversely related to age and was strongly associated with sex. Women required less warfarin than men, independent of age. The weekly maintenance warfarin dose for women at any given age was 4.5 mg lower than that of men. This might be explained by differences in mean body size, hepatic fat content or intrinsic differences in warfarin metabolism. However, the possible effect of weight could not be completely accounted for [1]. As dosing of warfarin is based on INR monitoring, these sex differences have little clinical impact.

Effects

A review shows that warfarin is at least equally effective in reducing the risk of thromboembolism in men and women [3]. In a large cohort study (8 850 men, 6 828 women), women with atrial fibrillation were at higher risk for incident thromboembolism than men with atrial fibrillation at both younger and older ages during off-warfarin periods. Adjusted RR for women versus men was 1.6 for those ≤ 75 years of age and 1.8 for those >75 years of age. Warfarin therapy was associated with a significant reduction in the rate of thromboembolism with an adjusted RR of 0.4 in women and 0.6 in men. In multivariable models including patients both on and off warfarin therapy, the reduction in rates of thromboembolism with warfarin was larger in women than in men [4].

Adverse effects

A cohort study (505 men, 275 women) observed that among patients with chronic warfarin treatment, women had higher risk of ischemic stroke than men. The RR of women compared to men was 2.0. The quality of the anticoagulation was similar in women and men [5].

Several studies, including a large meta-analysis, have shown that the major bleeding risk associated with warfarin is similar between men and women [3, 4, 6, 7]. However, a multicenter study (560 men, 339 women) in Canada showed that women on warfarin were 3.35 times more likely to experience a major bleed, compared to men [8].

Reproductive health issues 

Warfarin may interact with oral contraceptives. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).Warfarin can cause fetal harm when administrated to a pregnant woman. Regarding teratogenic aspects, please consult Janusmed Drugs and Birt Defects (in Swedish, Janusmed fosterpåverkan).

Other information

When Vitamin K oral anticoagulants where the only available oral anticoagulants, many studies found an under treatment in women with atrial fibrillation [8,9]. However, with introduction of new oral anticoagulants (NOACs) the utilization patterns of oral anticoagulant are now more equal between men and women [10].

Updated: 2018-12-18

Date of litterature search: 2018-04-04

References

  1. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest. 2005;127:2049-56. PubMed
  2. Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost. 2010;104:471-84. PubMed
  3. Fang MC, Singer DE, Chang Y, Hylek EM, Henault LE, Jensvold NG et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation. 2005;112:1687-91. PubMed
  4. Poli D, Antonucci E, Grifoni E, Abbate R, Gensini GF, Prisco D. Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment. Thromb Haemost. 2009;101:938-42. PubMed
  5. Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P et al. Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials. Eur Heart J. 2006;27:1947-53. PubMed
  6. Pancholy SB, Sharma PS, Pancholy DS, Patel TM, Callans DJ, Marchlinski FE. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol. 2014;113(3):485-90. PubMed
  7. Humphries KH, Kerr CR, Connolly SJ, Klein G, Boone JA, Green M et al. New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome. Circulation. 2001;103:2365-70. PubMed
  8. Jönsson AC, Ek J, Kremer C. Outcome of men and women after atrial fibrillation and stroke. Acta Neurol Scand. 2015;132(2):125-31. PubMed
  9. Wettermark B, Persson A, von Euler M. Secondary prevention in a large stroke population: a study of patients' purchase of recommended drugs. Stroke. 2008;39(10):2880-5. PubMed
  10. Loikas D, Forslund T, Wettermark B, Schenck-Gustafsson K, Hjemdahl P, von Euler M. Sex and Gender Differences in Thromboprophylactic Treatment of Patients With Atrial Fibrillation After the Introduction of Non-Vitamin K Oral Anticoagulants. Am J Cardiol. 2017;120(8):1302-1308. PubMed
  11. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-04-17.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson