Anticoagulants and bleeds Focus on older patients with AF Dr. Wilma - PowerPoint PPT Presentation

Anticoagulants and bleeds Focus on older patients with AF Dr. Wilma Knol, geriatrician University Medical Center Utrecht, the Netherlands

CONFLICT OF INTEREST DISCLOSURE I have no potential conflict of interest to report

Learning objectives The very old have higher risk of stroke ànd major • bleeding compared with younger adults The benefit of anticoagulants is highest in older patients • and outweighs the risk of major bleeding Among DOAC’s apixaban and endoxaban may be the • safest anticoagulants from GI bleeding perspective Balancing thromboembolism against the risk of bleeding • in older patients with atrial fibrillation involves more than scientific facts

Antihrombotic therapy for AF in older people • Prevalence of AF in 80+: 10-20% • AF is dangerous: – 5-fold increased of risk of stroke – Increased risk of mortality and morbidity due to thromboembolic events

Top 3 of Drugs that increase bleeding risk V itamine K A ntagonists used by 17% of 75+ D irect O ral A nti C oagulants used by 2.5% of 75+ Antiplatelets used by 40% of 75+ GIP 2015. ZIN Netherlands

DOACs and prescribing practices for AF Fohtung e.a. JAGS 2017

Mode of action: VKA Coumarin XIa Warfarin IXa VIIIa Va TF-VIIa Xa IIa fibrinogen fibrin

Mode of action: new OAC Coumarin XIa IXa VIIIa Pentasaccharide Va TF-VIIa Xa IIa Bivalirudine

Mode of actions: DOACs Coumarin XIa IXa VIIIa Pentasaccharide Va TF-VIIa Xa IIa fibrin Bivalirudin rivaroxaban dabigatran apixaban edoxaban

Appropriateness of OAC for AF in older people Studies Patients Patients Information on 65-75y 75-80 y geriatric syndromes VKA Acenocoumarol 0 - Phenprocoumon 0 - Warfarin 24 16443 24621 2 (1 MMSE, 1 frailty) DOAC Apixaban 2 4519 5005 - Dabigatran 1 5256 5318 - Rivaroxaban 1 2366 6581 - Endoxaban 4 5654 - Wehling e.a. Review in Drugs Aging 2017

MB risk DOACs vs Warfarin in 75+ Meta-analysis of 10 RCTs • 25,031 patients aged 75 years and older • Dabigatran (2 trials), rivaroxaban (5 trials), apixaban (2 • trials) compared to warfarin Indication: AF or VTE • Sardar et al, J Am Geriatr Soc 2014;62:857

Sardar et al, J Am Geriatr Soc 2014;62:857

Bleeding risk DOACs vs Warfarin in 75++ Meta-analysis of 11 RCTs • 31,418 patients aged 75 years and older • Dabigatran (5 trials), rivaroxaban (5), apixaban (4), endoxaban (5) • compared to warfarin Indication: AF or VTE • Mean CHADS2 ranged from 1.8-3.5 • Sharma e.a. Circulation. 2015;132:194-204

Sharma e.a. Circulation. 2015;132:194-204

MB risk DOACs vs Warfarin in 75+ Significant reduction of risk of MB in comparison with VKA • for apixaban = OR 0.63: 0.51-0.77 Significant reduction of risk of MB for endoxaban 60 mg = • OR 0.81: 0.67-0.98 and 30 mg = OR 0.46: 0.38-0.57 Dabigatran (150 and 110 mg) and rivaroxaban show a non- • significant higher risk of MB Sharma e.a. Circulation. 2015;132:194-204

Sharma e.a. Circulation. 2015;132:194-204

ENGAGE AF trial 75+ Kato e.a. J.Am. Heart Assoc. 2016

GIB risk DOACs vs Warfarin in 75+ Risk of secondary outcomes in older people: Significantly highe r GI bleeding risks with: • - dabigatran 150mg (OR 1.78: 1.35-2.35) - dabigatran 110mg (OR 1.40: 1.04-1.90) - endoxaban 60 mg (OR 1.32:1.01-1.72) Significant lower GI bleeding risk with: • - endoxaban 30 mg (OR 0.31: 0.15-0.87) Sharma e.a. Circulation. 2015 and Kato e.a. J Am. Heart Assoc. 2016

ICB risk DOACs vs Warfarin in 75+ Risk of secondary outcomes in older people: Significant reduction of ICB in comparison with VKA for • - dabigatran 150 mg (OR 0.43: 0.26-0.72) - dabigatran 110 mg (OR 0.36: 0.22-0.61) - apixaban (OR 0.38: 0.24-0.59) - endoxaban 60 mg (OR 0.40: 0.26-0.62) Sharma e.a. Circulation. 2015 and Kato e.a. J.Am. Heart Assoc. 2016

Real life data about GI bleeds with DOACs Population based study NVAF and naive to DOAC 2010-2015 Source population 43303 18+ 6576 apixaban • 17426 dabigatran 150 mg BID • 19301 rivaroxaban • 34.1-45.8% 75+ Using propensity matched cohorts Primairy outcome: GI bleed Abraham e.a. Gastroenterology 2017; 152:1014-1022

Real life data about bleeds in reduced doses DOACs Nation wide cohort study NVAF and naive to DOAC 2011-2016 • Source population 55644 4400 apixaban 2.5 mg • 8875 dabigatran 110 mg BID • 3476 rivaroxaban 15 mg • 38893 warfarin • Overall mean age was 73.9 (SD 12.7), ranging from a mean • of 71 (warfarin) to 83.9 (apixaban) Using propensity matched cohorts • Principal safety outcome : any bleeding event • Nielsen PB e.a. BMJ 2017

Real life data about bleeds in reduced doses DOACs The results on ischemic stroke were not significantly • different. Rates of bleeding were significantly lower for dabigatran • (HR 0.80: 0.70-0.92) Not significantly different for apixaban and rivaroxaban • compared with warfarin Nielsen PB e.a. BMJ 2017

Tromboembolic Risk vs Bleeding Outcomes Sub-analysis from PREFER in AF, prospective real-world registry from 461 hospitals in EU 2012-2014, 1y FU • 6412 AF patients total , 505 ≥85y • Antithrombotic therapies in 85+ • No therapy = 35 (6.9 %) OAC = 393 (77.8%) VKA = 362 (71.7%) DOAC = 31 (6.1%) Antiplatelet = 77 (15.3%) OAC+Antipl = 50 (9.9%) Patti e.a. J Am Heart Assoc 2017

Tromboembolic Risk vs Bleeding Outcomes Major bleeding events per 100 patients/y Highest bleeding risk in OAC+antiplatelet = 6.3 per 100 patients/y Patti e.a. J Am Heart Assoc 2017

Tromboembolic Risk vs Bleeding Outcomes The oldest patients getting the highest advantage: Patti e.a. J Am Heart Assoc 2017

OAT after GI Bleeding Thromboembolism Mortality Chai-Adisaksopha et al, Meta-analysis in Thromb Haemost 2015; 819-25

OAT after major bleeding Subgroup analysis of VENPAF, observational study in 798 elderly aged 80+ with NVAF and naive to VKA therapy Study period: 2007-2012 65 MB (3,4% patients/year,) • 16 fatal • Subgroup after MB From time of first MB 36 months FU or until TE, 2nd MB, or death No significant difference in age (84.6y), gender, TTR, comorbidities and CHA2DS2-VASc (mean 4.0 vs 4.3) and HAS-BLED scores (mean 2.8 vs 2.9) in restarted (N=25) vs discontinued (N=24) Zoppellaro e.a. Thromb Haemost 2017;117

OAT after major bleeding In restarted 2 MBs In discontinued 4 MB and 6 TE Persisted N=25 Discontinued N=24 Zoppellaro e.a. Thromb Haemost 2017;117

Modifiable and non modifiable risk factors 2016 ESC guideline AF

Learning objectives The very old have higher risk of stroke ànd major • bleeding compared with younger adults The benefit of anticoagulants is highest in older patients • and outweighs the risk of major bleeding Among DOAC’s apixaban and endoxaban may be the • safest anticoagulants from GI bleeding perspective Balancing thromboembolism against the risk of bleeding • in older patients with atrial fibrillation involves more than scientific facts

Reversal agents for DOACs Idarucizumab (Praxbind) 5 gr iv rapidly and completely • reverses the anticoagulant effect of dabigatran Andexanet alfa, a recombinant modified human factor • Xa decoy protein neutralized the anticoagulant effects of both direct and indirect factor Xa inhibitors within minutes after infusion (not yet approved for use)

Comparison of bleeding risk scores Yao et al AmJ Cardiol 2017