21-12-17

1

DOACS ANNO 2017CLOSING THE GAPS

PeterVerhammeBloedings- enVaatziekten

UZLeuven

NOACS ANNO 2017

NOACs have replaced warfarin as the recommended/preferred anticoagulationfor patients with Atrial Fibrillation

NOACs have replaced warfarin as the recommended/preferred anticoagulation for patients with Venous Thromboembolism

ESC,AHA,ISTH&ACCPguidelines

21-12-17

2

COUMARINE VAN MARC

21-12-17

3

NIEUWE BLOEDVERDUNNERS

DABIGATRAN (PRADAXA)RIVAROXABAN (XARELTO)APIXABAN (ELIQUIS)EDOXABAN (LIXIANA)

Rivaroxaban Versus ASA for Extended Treatment of VTE

30-dayfollow-up

Rivaroxaban 10 mg od

n=1136

ASA 100 mg od

n=1139

12-month planned treatment duration†

Population: Patients with confirmed symptomatic PE/DVT

who completed6–12 months’

anticoagulation*

RN=3396

Rivaroxaban 20 mg od

n=1121

Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

21-12-17

4

RIVA 20 OR RIVA 10 MG OR ASA FOR EXTENDEDTREATMENT OF VTE?

Intention-to-treatanalysisWeitzJIetal,NEnglJMed 2017:doi:10.1056/NEJMoa1700518

ASA100mgod

Rivaroxaban 20mgod

Rivaroxaban10mgod

Days

0

1

2

3

4

5

Cumulativeincide

nce(%

)

1 30 60 90 120 150 180 210 240 270 300 330 367

Rivaroxaban 20 mg od vs ASA1.5%vs 4.4%HR=0.34(95%CI0.20–0.59),p<0.001

Rivaroxaban 10 mg od vs ASA1.2%vs 4.4%HR=0.26(95%CI0.14–0.47),p<0.001

RATES OF MAJOR BLEEDING WERE ≤0.5% ANDSIMILAR TO ASA

Safetyanalysis.NoeventsafterDay360uptoDay480WeitzJIetal,NEnglJMed 2017:doi:10.1056/NEJMoa1700518

0

1

2

4

5

3

Days

ASA100mgod

Rivaroxaban20mgodRivaroxaban10mgod

1 30 60 90 120 150 180 210 240 270 300 330 360

Cumulativeincide

nce(%

)

Rivaroxaban 20 mg od vs ASA6/1107 (0.5%) vs 3/1131 (0.3%)HR=2.01 (95% CI 0.50–8.04), p=0.32

Rivaroxaban 10 mg od vs ASA5/1127 (0.4%) vs 3/1131 (0.3%)HR=1.64 (95% CI 0.39–6.84), p=0.50

21-12-17

5

AMPLIFY EXTENSION Study

Agnelli G, et al. N Engl J Med 2012; 368:699–708.

Apixaban(2.5 mg BID)

Apixaban(5 mg BID) Placebo

Recurrent VTE 1.7% 1.7% 8.8%

Major bleeding 0.2% 0.1% 0.5%

Non-major bleeding 3.0% 4.2% 2.3%

STEPPED DOWN TREATMENT OF VTE

Initial treatment

Treatment dose Prevention dose

Initial1–3 weeks

Long-term3–6 months

ExtendedBeyond 6 months

21-12-17

6

STEPPED DOWN TREATMENT OF VTE

Initial treatment

Treatment dose Prevention dose

Initial1–3 weeks

Long-term3–6 months

ExtendedBeyond 6 months

Rivaroxaban 15mg BD 3wk 20 (15) mg OD 10mg ODApixaban 10mg BD 1wk 5mg BD 2.5mg BDEdoxaban LMWH 1wk 60 (30) mg ODDabigatran LMWH 1wk 150 (110) mg BD

Treatment of Frail* VTE Patients ?

4,5

1,11,30,9

0

1

2

3

4

5

6

Frail Non-frail

Maj

or b

leed

ing

(%)

0,1 1 10

*One or more of: >75 years old, CrCl <50 ml/min, low body weight (≤50 kg); #safety population (N=8246); frail patients (n=1567); ‡ITT population (N=8281); frail patients (n=1573)

Prins MH et al, Thromb J 2013;11:21

Efficacy:frail‡

Efficacy:non-frail‡

Majorbleeding: frail#

Majorbleeding:non-frail#n=10n=35 n=30n=37

RivaroxabanEnoxaparin/VKA

73%RRR‡

3.2% ARR

Favoursrivaroxaban

FavoursEnox/VKA

EINSTEIN DVT and EINSTEIN PE pooled analysis

21-12-17

7

Pulmonary embolism in patients right ventricular dysfunction

RV dilatation Cardial biomarkerNT-proBNP

Lancet Haematology 2016

Recurrent in patients with comorbidities and polypharmacy

RV dilatation Cardial biomarkerNT-proBNP

0 30 60 90 120 150 180 210 240 270 300 330 360

Days from Randomization

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Rec

urre

nt V

TE (%

)

Heparin/Warfarin/3.>5PriorMedsHeparin/Edoxaban/3.>5PriorMeds

group

At least 5 concomittant medicationsat baseline

0 30 60 90 120 150 180 210 240 270 300 330 360

Days from Randomization

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Rec

urre

nt V

TE

(%

)

Heparin/Warfarin/3.>2MedHisHeparin/Edoxaban/3.>2MedHis

group

At least 2 medicalcomorbidities

Vanassche, ISTH 2017

21-12-17

8

NOACS ANNO 2017

NOACs have replaced warfarin as the recommended/preferred anticoagulation for patients with Venous Thromboembolism

except: PregnancyPreventionCancer

uncertainty: Severe renal insufficiency Drug Drug Interactions

NOACS ANNO 2017

NOACs have replaced warfarin as the recommended/preferred anticoagulationfor patients with Atrial Fibrillation

except: Mechanical Heart Valve

uncertainty: Optimal dosing in frailtySevere renal insufficiency CrCl < 15 ml/min

Drug Drug InteractionsAntiplatelet therapy

21-12-17

9

100% 50% 0% -50% -100%

AFASAK-1(671)

SPAF(421)

BAATAF(420)

CAFA(378)

SPINAF(571)

EAFT(439)

AllTrials(n=6;2900)

WarfarinBetter WarfarinWorse

64%

HartRG,etal.AnnInternMed.2007;146:857-867.[29]

STROKE PREVENTION IN AF WARFARIN VSPLACEBO

RCTS AND REAL-WORLD DATANOACS COMPARED WITH VKA IN AF

OutcomeRandomizedtrials RealWorldData

Risk Ratio 95%CI RiskRatio 95%CIMajor

bleeding 0.85 0.73-1.00 0.91 0.79-1.05

Strokeorembolism 0.79 0.72-0.87 0.88 0.83-0.94

Death 0.90 0.86-0.96 0.71 0.58-0.87

4 randomized trials, >70,000 patients10 studies RealWorldData, 494,964 patients

Li G, et al. Eur J Epidemiol 2016; 31; 541-561.

21-12-17

10

Bafta Study,Lancet,2008.

NOACS FOR STROKE PREVENTION IN >75 ?

NOAC VS. WARFARIN (22371 PATIENTS)HR 0.71 (0.62-0.83)

21-12-17

11

Ann Intern Med 2009

Netclinical Benefitby Age

Alexander,JACC,2016

NIERINSUFFICIENTIE?Warfarin

vs.Apixaban

21-12-17

12

GEBRUIK VAN GEREDUCEERDE DOSIS?

Pradaxa ROCKETXarelto ARISTOTLEEliquis ENGAGELixiana

% dosisreductie 2X150mg2X110

-20%(20 – 15mg)

-50%(2X5– 2X2.5mg)

-50%60– 30mg30– 15mg

criteria randomizatie

Kliniek:>75(80)

klaring<50ml/min 2vande3:- leeftijd ≥80- gewicht≤60- creat ≥1.5mg/dL

randomizatie naar60of30mg,verder50%reductiebij1vande3:- klaring<50ml/min- gewicht60kg- gebruikvanP-gp-

inhibitorpatiëntenmetgereduceerde dosis(%)

(33%) 20.7% 4.7% 25%

NOACs vs VKA: Improved Clinical outcomes

Ruff CT et al, Lancet 2014;383:955–962

Pooled NOAC

(events)

Pooled warfarin (events)

RR(95% CI) p-value

Efficacy

Ischaemic stroke 665/29,292 724/29,221 0.92 (0.83–1.02) 0.10

Haemorrhagic stroke 130/29,292 263/29,221 0.49 (0.38–0.64) <0.0001

Myocardial infarction 413/29,292 432/29,221 0.97 (0.78–1.20) 0.77

All-cause mortality 2022/29,292 2245/29,221 0.90 (0.85–0.95) 0.0003

SafetyIntracranial haemorrhage

204/29,287 425/29,211 0.48 (0.39–0.59) <0.0001

Gastrointestinal bleeding

751/29,287 591/29,211 1.25 (1.01–1.55) 0.043

Favours NOAC

Favours warfarin

210.50.2

21-12-17

13

Increased risk of stroke correlates with increased risk of bleeding on treatment with anticoagulant

1. Non-anticoagulated patients. Gage BF et al. JAMA 2001;285:2864–2870; 2. Patients anticoagulated with rivaroxaban. Peacock WF et al. Ann Emerg Med 2017;69:541–550.e1.

CHADS2 Score

CHA2DS2-VASc Score

1,9% 2,8%4,0%

5,9%8,5%

12,5%

18,2%

0%

5%

10%

15%

20%

0 1 2 3 4 5 6

Adjusted Stroke Rate (%/year)

0,3% 0,7% 1,0% 1,8%3,2%

5,4%

0%

5%

10%

15%

20%

0 1 2 3 4 ≥ 5

Major Bleeding rate (%/year)

1

2

Ageand Riskfor MajorBleeding

Warfarinvs.

Apixaban

21-12-17

14

Clinically relevant bleeding of Edoxaban vs Warfarin in Patients With & Without Increased Risk of Falls

Endpoint Edoxaban(n=310)

Warfarin(n=307)

Hazard ratio(95% CI) pinteraction

22 (2.81) 22 (2.85) 0.96 (0.53–1.75)

Major + CRNM bleeding

103 (21.74) 127 (26) 0.83 (0.64–1.08)0.76

1472 (10.92) 1683 (12.72) 0.86 (0.80–0.93)

0,5 1 1,5 2

Increased fall riskNo increased fall risk

Values are number of events and event rates (%/year). CRNM = clinically relevant non-major bleeding; SEE = systemic embolic events. Steffel et al. J Am Coll Cardiol. 2016;68:1169–78

Bleeding While on an Anticoagulant: What Have We Learnt?

uLess critical bleeding with NOACs uDifferent bleeding pattern with NOACsuPatient characteristics drive bleedinguProactive measures to reduce bleeding riskuGuidance to manage bleeding

21-12-17

15

aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time. Pollack et al. N Engl J Med 2017

RE-VERSE AD: immediate, complete, and sustained reversal of dabigatran

No idarucizumab-related prothrombotic effects

identified to date

Normal intraoperative haemostasis achieved in 93% of Group B patients

who underwent procedures

Group A: Uncontrolled bleeding (n=293)

Group B: Emergency surgery or procedure (n=195)

10th/90th percentiles 5th/95th percentilesMedian and 25th/75th percentiles Assay upper limit of normal

Time post-idarucizumab

dTT

(s)

110

70

60

50

40

30

100

90

80

1 h 2 h 4 h 12 h 24 hBaselineBetweenvials

10–30min

0

Idarucizumab 2×2.5 g

120

dTT

(s)

30

1 h 2 h 4 h 12 h 24 hBaselineBetweenvials

10–30min

0

Time post-idarucizumab

Idarucizumab 2×2.5 g

110

70

60

50

40

100

90

80

120

NOACS IN 2017: WAT NA PCI?

Dabigatran Dual Therapy or Warfarin Bi/Triple Therapy

RE-DUAL PCI, NEJM 2017

21-12-17

16

Gibson CM et al, New Engl J Med 2016; doi: 10.1056/NEJMoa1611594]

TIM

I maj

or, T

IMI m

inor

or b

leed

ing

requ

iring

med

ical

atte

ntio

n (%

)

Time (days)

Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=0.59; (95% CI 0.47–0.76); p<0.001Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.63 (95% CI 0.50–0.80); p<0.001

30

25

20

15

10

5

00 30 60 90 180 270 360

26.7%

18.0%16.8%

Group 2 (Rivaroxaban 2.5 mg BID plus DAPT)Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet)

Group 3 (VKA plus DAPT)

ARR8.7%

ARR9.9%

NNT=12

NNT=11

NOACS IN 2017: WAT NA PCI?

Bleeding While on an Anticoagulant: What Have We Learnt?

uLess critical bleeding with NOACs uDifferent bleeding pattern with NOACsuPatient characteristics drive bleedinguProactive measures to reduce bleeding riskuGuidance to manage bleeding