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

Antiplatelets used by 40% of 75+

GIP 2015. ZIN Netherlands

Vitamine K Antagonists used by 17% of 75+ Direct Oral AntiCoagulants used by 2.5% of 75+

DOACs and prescribing practices for AF

Fohtung e.a. JAGS 2017

TF-VIIa Xa IIa fibrin XIa IXa fibrinogen Va VIIIa

Coumarin Warfarin

Mode of action: VKA

TF-VIIa Xa IIa XIa IXa Va VIIIa

Coumarin Pentasaccharide Bivalirudine

Mode of action: new OAC

TF-VIIa Xa IIa Va fibrin IXa Coumarin Pentasaccharide Bivalirudin rivaroxaban apixaban edoxaban dabigatran

Mode of actions: DOACs

VIIIa XIa

Appropriateness of OAC for AF in older people

Studies Patients 65-75y Patients 75-80 y Information on geriatric syndromes VKA Acenocoumarol

• Phenprocoumon
• 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 higher 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
• f 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

Patti e.a. J Am Heart Assoc 2017

Highest bleeding risk in OAC+antiplatelet = 6.3 per 100 patients/y

Tromboembolic Risk vs Bleeding Outcomes

The oldest patients getting the highest advantage:

Patti e.a. J Am Heart Assoc 2017

Chai-Adisaksopha et al, Meta-analysis in Thromb Haemost 2015; 819-25

OAT after GI Bleeding

Thromboembolism Mortality

OAT after major bleeding

Subgroup analysis of VENPAF,

• bservational 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

• r 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

Zoppellaro e.a. Thromb Haemost 2017;117

Persisted N=25 Discontinued N=24

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