Drug products: Pradaxa
ATC code: B01AE07
Substances: dabigatran, dabigatran etexilate, dabigatran etexilate mesylate
Dabigatran use at both doses (110 mg and 150 mg) have similar effects in men and women with atrial fibrillation. A higher bleeding risk has been observed in women but not in men treated with dabigatran. There is an increased risk of bleeding in patients older than 75 years and in patients with a body weight below 50 kg. Monitoring signs of bleeding in these groups seems prudent. Dose adjustment may be considered in women of high age and/or with low body weight.
Pharmacokinetics and dosing
Following a single 150 mg dabigatran dose, healthy women achieved a higher plasma concentration than healthy men, 163 ng/ml and 67.9 ng/ml respectively. The plasma concentration was on average 30-50% higher in women than in men . Among the elderly (>65 years old), the AUC of dabigatran was 20-30% higher in women than in men. This can be explained by the sex difference in kidney function as indicated by a difference in creatinine clearance . In primary VTE (venous thromboembolism) prevention studies, the exposure of dabigatran was 40-50% higher in women than in men. In atrial fibrillation (AF) patients, women had on average 30% higher trough and post-dose concentrations . Similarly, an exposure-response analysis from the RE-LY trial showed that women had approximately 50% higher plasma concentrations of dabigatran than men . Another analysis from the RE-LY trial (6190 men, 3332 women) found 9.1% higher AUC in women than men and 8.3% lower apparent clearance .Despite observed sex differences in dabigatran pharmacokinetics, no general dose adjustment based on sex is currently recommended . However, the risk of bleeding is higher in patients ≥75 years of age and in patients with body weight <50 kg and therefore it may be appropriate to be observant for signs of bleeding in women due to age or body weight and to consider dose adjustment [14, 15, 17].
New oral anticoagulantsIn atrial fibrillation (AF) patients, large meta-analyses of phase III trials have found that NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) are better than warfarin in preventing stroke and systemic embolism in both men and women [1-3]. In contrast, a meta-analysis on data from other phase III trials (in total 18 415 men, 13 094 women) on NOACs (apixaban, dabigatran, ximelagatran), found that men were more protected from stroke or systemic embolism than women . An observational study on AF patients in Hong-Kong (4972 men, 4834 women) showed that use of NOACs (apixaban, dabigatran, rivaroxaban) was associated with lower all-cause mortality in women but not in men, when compared to warfarin . However, risk of stroke and response to thrombolytic therapy may vary between ethnic groups, and a higher risk of bleeding in Asians treated with warfarin has been reported . Similarly, another meta-analysis found a higher risk of stroke and systemic embolism in women treated with NOAC (apixaban, dabigatran, edoxaban, rivaroxaban) .In venous thromboembolism (VTE) patients, two sex-specific meta-analyses on NOACs (apixaban, dabigatran, edoxaban, rivaroxaban, ximelagatran) have found no sex difference in the rate of VTE recurrence [7, 8]. Specific for dabigatranIn the multinational Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study (11 514 men, 6 599 women), dabigatran 150 mg daily reduced stroke incidence in AF patients better than warfarin, while dabigatran 110 mg daily had similar effect on risk of stroke as warfarin. No sex difference in outcome was observed for any of the doses. However, few women participated in the study .Similarly, a sex-specific Canadian observational study (31 324 men, 31 786 women) observed no sex differences in risk of stroke in AF patients for any of the dabigatran doses, when compared with warfarin. Women were less likely to be prescribed dabigatran compared with warfarin, and women receiving dabigatran were more likely to be prescribed the lower dose, although women had a higher baseline risk of stroke than men, .Sex-specific effects of dabigatran were compared with rivaroxaban and warfarin in a large American cohort study with AF patients (65 734 men, 81 135 women). Dabigatran and rivaroxaban reduced heart failure admissions and all-cause mortality in both men and women, when compared with warfarin. In men, rivaroxaban reduced myocardial infarction (MI) admissions compared to warfarin and dabigatran. In women, no difference in MI admissions between the three anticoagulants were seen . These differences may reflect selection bias in choosing anticoagulant rather differences in the individual anticoagulants.
New oral anticoagulantsA sex-specific meta-analysis on the risk of bleeding from anticoagulants in patients with AF or VTE (57 043 men, 37 250 women) found a similar bleeding risk in men and women . However, sex differences have been observed when analyzing by indication, as described below.In AF patients, a worldwide meta-analysis (16 760 men, 9 500 women) found that women treated with NOACs (apixaban, dabigatran, rivaroxaban) had lower risk of major bleeding than men, while women treated with warfarin had similar risk of bleeding as men . Similarly, another meta-analysis found a lower risk of major bleeding in women (apixaban, dabigatran, edoxaban, rivaroxaban) even after omitting the AVERROES study using aspirin as comparator . Contrary to this, another meta-analysis, including the same studies, found no sex differences in major bleeding events from NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), when compared with warfarin . Also, an observational study conducted in Hong-Kong (4972 men, 4834 women) showed that use of NOAC (apixaban, dabigatran, rivaroxaban) was associated with a lower risk of intracranial hemorrhage in women but not in men, when compared with warfarin. The risk of GI bleeding was similar in men and women treated with NOAC, when compared with warfarin .In VTE patients, a sex-specific meta-analysis (43.7% women) found that women had more bleeding events from NOACs (apixaban, rivaroxaban, ximelagatran) than men . Another sex-specific meta-analysis on VTE (13 139 men, 9814 women) found a higher risk of bleeding in women than in men from both warfarin and NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) . However, another similar meta-analysis of the same studies showed that the sex difference in incidence of bleedings was only significant for edoxaban (RR 0.52) [8, 11]. Specific for dabigatranAnalyzes on plasma concentrations from the RE-LY study showed that major bleeding was impacted by “age and concomitant antiplatelet use, with patient’s sex, history of diabetes, and CAD also significant covariates in the model” . In a Canadian observational study on AF patients (31 324 men, 31 786 women), both doses of dabigatran were associated with a lower risk of bleeding events (intracranial hemorrhage, gastrointestinal hemorrhage, other hemorrhage) in men but not in women, as compared to warfarin, although the association with the higher dabigatran dose in women was almost statistically significant (HR 0.85, 95% CI 0.71-1.01). Women had a lower bleeding risk at baseline and were more likely to dispense the lower dabigatran dose . Another observational study on AF patients treated with dabigatran found men to have a lower risk of GI bleeding. However, more women had experienced a GI bleeding event at baseline .
Reproductive health issues
Regarding teratogenic aspects please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2018-07-30
- Ahmad Y, Lip GY, Apostolakis S. New oral anticoagulants for stroke prevention in atrial fibrillation: impact of gender, heart failure, diabetes mellitus and paroxysmal atrial fibrillation. Expert Rev Cardiovasc Ther. 2012;10(12):1471-80. PubMed
- 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
- Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-62. PubMed
- Proietti M, Cheli P, Basili S, Mazurek M, Lip GY. Balancing thromboembolic and bleeding risk with non-vitamin K antagonist oral anticoagulants (NOACs): A systematic review and meta-analysis on gender differences. Pharmacol Res. 2017;117(1):274-282. PubMed
- Law SWY, Lau WCY, Wong ICK, Lip GYH, Mok MT, Siu CW et al. Sex-Based Differences in Outcomes of Oral Anticoagulation in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2018;72(3):271-282. PubMed
- Raccah BH, Perlman A, Zwas DR, Hochberg-Klein S, Masarwa R, Muszkat M et al. Gender Differences in Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Network Meta-analysis. Ann Pharmacother. 2018;52(11):1135-1142. PubMed
- Alotaibi GS, Almodaimegh H, McMurtry MS, Wu C. Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis. Thromb Res. 2013;132(2):185-9. PubMed
- Loffredo L, Violi F, Perri L. Sex related differences in patients with acute venous thromboembolism treated with new oral anticoagulants A meta-analysis of the interventional trials. Int J Cardiol. 2016;212:255-8. PubMed
- Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(5):595-605. PubMed
- Gómez-Outes A, Terleira-Fernández AI, Lecumberri R, Suárez-Gea ML, Vargas-Castrillón E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2014;134:774-82. PubMed
- Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15. PubMed
- Stangier J, Stähle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48:1411-9. PubMed
- Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47:47-59. PubMed
- Pradaxa (dabigatran). Summary of Product Characteristics. European Medicines Agency (EMA) [updated 2018-06-15, cited 2018-07-30].
- Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321-8. PubMed
- Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost. 2011;9(11):2168-75. PubMed
- Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51. PubMed
- Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Pilote L. Sex Differences in Dabigatran Use, Safety, And Effectiveness In a Population-Based Cohort of Patients With Atrial Fibrillation. Circ Cardiovasc Qual Outcomes. 2015;8:593-9. PubMed
- Shantha GPS, Mentias A, Bhise V, Kumar A, Rasmussen T, Adams C et al. Gender Differences in the Trends of Hospitalizations for Acute Stroke Among Patients With Atrial Fibrillation in the United States: 2005 to 2014. Am J Cardiol. 2017;120(9):1541-1548. PubMed
- Lauffenburger JC, Rhoney DH, Farley JF, Gehi AK, Fang G. Predictors of gastrointestinal bleeding among patients with atrial fibrillation after initiating dabigatran therapy. Pharmacotherapy. 2015;35(6):560-8. PubMed
- Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-07-24.] länk
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson