Table S2 Sex- specific differences in oral anticoagulant prescription for stroke prevention in AF Total sample size (% women) Anticoagulant(s) studied Gage (2000) 1 Missouri, USA Discharged during 597 (54.9%) Warfarin Oct 1993 Aspirin Medicare Dec 1994 beneficiaries with chronic nonvalvular AF at Missouri hospitals Overall antithrombotic : Warfarin: 34% Aspirin: 21% Neither: 45% Women: Warfarin: 29% Aspirin: 21% Humphries (2001) 2 CARAF Six cities across Canada Patients recruited at physicians offices, emergency departments, and during hospital admission at first ECG- confirmed diagnosis of AF Enrolment during 1990 1994 899 (37.7%) Warfarin Aspirin Women less likely to receive antithrombotic than men (P = 0.02) Women aged 75 years were less likely to receive warfarin but more likely to receive aspirin than men aged 75 years. There was a significant interaction between age 75 years and sex for antithrombotic use (P = 0.025 for interaction) Among patients aged 75 years with 1 stroke risk factor, men (44.9%) more likely to be receiving warfarin than women (24.5%; P = 0.034) Page 1 of 9
Simpson (2005) 3 Scotland (61 primary care practices) Walker (2008) 4 Niska (2009) 5 Patients with computer record of transient cerebral ischaemia or any stroke, including cerebral infarction and other stroke USA Patients aged 40 years with AF or atrial flutter covered for both medical and pharmacy services by a large health plan USA Patients with AF aged 20 years randomly sampled from 112 geographical primary sampling units Implementation of secondary preventive between March 2003 and April 2004 Insurance claim during January 1999 June 2005 Visit files during 2001 2006 10,076 (52.4%) Warfarin Antiplatelet 116,969 (41.0%) Warfarin Antiplatelet 1,171 (47.9%) Warfarin Aspirin Page 2 of 9 Overall 76.8% of patients with ischaemic stroke patients received either antiplatelet or warfarin Women with ischaemic stroke were less likely to receive either an antiplatelet or warfarin than men (OR 0.84, 95% CI 0.75 0.94) Women with AF were less likely to receive warfarin (OR 0.62, 95% CI 0.48 0.81) and more likely to receive antiplatelet than men (OR 1.30, 95% CI 1.00 1.68) Overall antithrombotic : Warfarin: 45% Antiplatelet: 6% Neither: 48% Men were more likely to be dispensed an anticoagulant than women (OR 1.46, 95% CI 1.40 1.52) Overall antithrombotic : Warfarin: 52.2% Aspirin: 15.9% Women less likely to be prescribed warfarin than men (OR 0.69, 95% CI 0.50 0.94)
Agarwal (2010) 6 USA In- patients aged 40 years diagnosed with AF during hospitalization, from approximately 250 hospitals Hospitalization between November 2003 and October 2004 44,193 (51.5%) Warfarin Unfractionated heparin Low- molecular heparin Overall warfarin use: 56.2% Women less likely to receive warfarin (OR 0.96, 95% CI 0.92 1.00, P = 0.0337) No sex- specific differences for warfarin use in patients aged 75 years (OR 0.95, 95% CI 0.90 1.01, P = 0.1164) Inoue (2010) 7 J- TRACE 10 regions in Japan Patients aged 20 90 years with at least 1 3 cardiovascular diseases (stroke, MI, or AF) January 2005 December 2006 2,892 (29.9%) Warfarin Antiplatelet (aspirin, ticlopidine, cilostazol) Women less likely to receive other anticoagulants (OR 0.93, 95% CI 0.89 0.97, P = 0.0004) No sex- specific differences in the use of warfarin at baseline Women: 72.7% Men: 73.1% P = 0.807 No sex- specific differences in the use of aspirin, ticlopidine, cilostazol at baseline Women: 30.8%, 5.0%, 1.3% Men: 32.1%, 5.0%, 2.0% P = 0.504, 0.316, 0.191 Page 3 of 9
Sjolander (2012) 8 Raji (2013) 9 Lee (2015) 10 Sweden Patients with ischaemic stroke from the Swedish Stroke Register with information on prescription of secondary preventive drugs USA Medicare beneficiaries aged 65 years with AF and atrial flutter South Korea Patients with AF or atrial flutter and high risk of thromboembolism (CHADS 2 2) from the Korean Health Insurance Service July 2005 June 2006 18,349 (49.1%) Warfarin Antiplatelet Men more likely to be prescribed warfarin than women (38.4% vs 26.4%; age- adjusted prevalence ratio 0.88, 95% CI 0.79 0.97) No sex- specific differences in antiplatelet treatment (men 81.3%, women 82.6%; age- adjusted prevalence ratio 1.02 95% CI 0.98 1.05) 2007 2008 41,447 (60.4%) Warfarin Overall warfarin use: 66.8% Women: 65.6% Men: 68.7% P <0.001 2009 8,475 (48.6%) Warfarin Aspirin No sex- specific difference for warfarin use after multivariable adjustment (OR 1.04, 95% CI 0.99 1.09) Women more likely to underutilize warfarin* (OR 1.27, 95% 1.14 1.42, P <0.0001) No sex- specific difference for aspirin* underutilization (adjusted OR 1.09, 95% CI 1.00 1.20, P = 0.0617) Page 4 of 9
Lip (2015) 11 GARFIELD- AF 30 countries (Europe, Asia, Central/South America, Canada, Australia, South Africa) Aged 18 years with nonvalvular AF and 1 additional factor(s) for stroke Enrolment during March 2010 June 2013 Total sample size (% women) 17,184 (43.8%) Europe 63.1% Asia 23.0% Central/South America 8.4% Canada 2.0% Australia 2.5% South Africa 1.0% Anticoagulant(s) studied Vitamin K antagonists Oral, injectable, or undefined factor Xa inhibitors Direct thrombin inhibitors Overall rate of use similar in women (60.8%) and men (60.0%) Rate of NOAC use similar in women (11.7%) and men (11.8%) Rate of antiplatelet use alone similar in women (27.2%) and men (28.0%) For women with CHA 2 DS 2 - VASc = 1 (41.1%) and men with CHA 2 DS 2 - VASc=0 (41.8%) the rate of anticoagulant use was similar For women (64.6%) and men (61.6%) with CHA 2 DS 2 - VASc = 2, the rate of anticoagulant use was similar Among patients with CHADS 2 2, anticoagulant use was similar in women and men (OR 1.00, 95% CI 0.92 1.09) Page 5 of 9
Patel (2015) 12 GWTG- STROKE Olesen (2015) 13 1,542 hospitals in the USA Patients with AF hospitalized for ischaemic stroke (79.1%) or TIA (20.9%) and discharged receiving warfarin or NOAC Denmark, nationwide OAC- naive patients with AF, aged 30 100 years, who were initiated on OAC Discharged during October 2010 September 2012 Initiated on OAC during August 2011 October 2013 61,655 (53.1%) Dabigatran Rivaroxaban Warfarin 18,611 (45.3%) Vitamin K antagonists Dabigatran Rivaroxaban Apixaban Overall OAC use: Warfarin: 88.9% Dabigatran: 9.6% Rivaroxaban: 1.5% Women: Dabigatran or rivaroxaban: 51.8% Warfarin: 53.3% No difference in the discharge prescription of dabigatran or rivaroxaban vs warfarin between women and men (OR for women vs men 0.94, 95% CI 0.88 1.01, P = 0.1) Overall OAC use: Warfarin: 53.2% Dabigatran: 38.3% Rivaroxaban: 7.0% Apixaban: 1.5% Women: Warfarin: 43.4% Dabigatran: 46.5% Rivaroxaban: 52.1% Apixaban: 51.1% P <0.001 Men less likely to be prescribed NOAC than women (OR 0.88, 95% CI 0.83 0.94, P <0.001) Page 6 of 9
Avgil Tsadok Quebec, Canada (2015) 14 Patients discharged after hospitalization with diagnosis of AF Discharged during January 1999 March 2013 63,110 (50.4%) Dabigatran Warfarin Dabigatran 110 mg Women: 64.8% Men: 48.2% Dabigatran 110 mg Aged <75 years: Women: 22.8% Men: 18.5% Aged >75 years: Women: 83.5% Men: 76.0% Hsu (2016) 15 PINNACLE USA, nationwide, office- based Patients with AF and CHADS 2 score 2 or CHA 2 DS 2 - VASc score 2 who are receiving aspirin or oral anticoagulation Enrolment during January 2008 December 2012 CHADS 2 score 2: 210,380 (46%) CHA 2 DS 2 - VASc score 2: 294,642 (46%) Warfarin NOAC Women more likely to receive dabigatran 110 mg compared with men even after adjusting for age and baseline comorbidities (OR 1.35, 95% CI 1.24 1.48) CHADS 2 score 2: Men more likely to receive OAC than aspirin compared with women (RR of aspirin vs OAC for men 0.93, 95% CI 0.92 0.94) CHA 2 DS 2 - VASc score 2: Men more likely to receive OAC than aspirin compared to women (RR of aspirin vs OAC for men 0.91, 95% CI 0.90 0.92) Page 7 of 9
Bo (2016) 16 Italy Patients aged 65 years with primary or secondary AF at a single hospital in Turin Discharged during 2010 2013 1,078 (60.3%) Vitamin K antagonists Female sex not a significant factor for warfarin prescription in univariate analysis *Warfarin and aspirin underutilization defined as never having been prescribed warfarin or aspirin, respectively, if the patient has a CHADS 2 score 2. AF, atrial fibrillation; ECG, electrocardiogram; MI, myocardial infarction; NOAC, non- vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; TIA, transient ischaemic attack. 1. Gage, B. F. et al. Adverse outcomes and predictors of underuse of antithrombotic in medicare beneficiaries with chronic atrial fibrillation. Stroke 31, 822 827 (2000). 2. Humphries, K. H. et al. New- onset atrial fibrillation: sex differences in presentation, treatment, and outcome. Circulation 103, 2365 2370 (2001). 3. Simpson, C. R., Wilson, C., Hannaford, P. C. & Williams, D. Evidence for age and sex differences in the secondary prevention of stroke in Scottish primary care. Stroke 36, 1771 1775 (2005). 4. Walker, A. M. & Bennett, D. Epidemiology and outcomes in patients with atrial fibrillation in the United States. Heart Rhythm 5, 1365 1372 (2008). 5. Niska, R. & Han, B. Anticoagulation for patients with atrial fibrillation in ambulatory care settings. J. Am. Board Fam. Med. 22, 299 306 (2009). 6. Agarwal, S., Bennett, D. & Smith, D. J. Predictors of warfarin use in atrial fibrillation patients in the inpatient setting. Am. J. Cardiovasc. Drugs 10, 37 48 (2010). 7. Inoue, H. et al. Sex- related differences in the risk factor profile and medications of patients with atrial fibrillation recruited in J- TRACE. Circ. J. 74, 650 654 (2010). 8. Sjolander, M., Eriksson, M. & Glader, E. L. Few sex differences in the use of drugs for secondary prevention after stroke: a nationwide observational study. Pharmacoepidemiol. Drug Saf. 21, 911 919 (2012). 9. Raji, M. A. et al. National utilization patterns of warfarin use in older patients with atrial fibrillation: a population- based study of Medicare Part D beneficiaries. Ann. Pharmacother. 47, 35 42 (2013). 10. Lee, I. H., Kim, H. & Je, N. K. Underutilization of warfarin for stroke prophylaxis in patients with atrial fibrillation or atrial flutter in Korea. J. Cardiol. 66, 475 481 (2015). 11. Lip, G. Y. et al. Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD- Atrial Fibrillation. Circ. Cardiovasc. Qual. Outcomes 8, S12 S20 (2015). 12. Patel, P. A. et al. Novel oral anticoagulant use among patients with atrial fibrillation hospitalized with ischemic stroke or transient ischemic attack. Circ. Cardiovasc. Qual. Outcomes 8, 383 892 (2015). Page 8 of 9
13. Olesen, J. B. et al. Non- vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011-2013. Europace 17, 187 193 (2015). 14. Avgil Tsadok, M., Jackevicius, C. A., Rahme, E., Humphries, K. H. & Pilote, L. Sex differences in dabigatran use, safety, and effectiveness in a population- based cohort of patients with atrial fibrillation. Circ. Cardiovasc. Qual. Outcomes 8, 593 599 (2015). 15. Hsu, J. C. et al. Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke. J. Am. Coll. Cardiol. 67, 2913 2923 (2016). 16. Bo, M. et al. Health status, geriatric syndromes and prescription of oral anticoagulant in elderly medical inpatients with atrial fibrillation. Geriatr. Gerontol. Int. http://dx.doi.org/10.1111/ggi.12730 (2016). Page 9 of 9