DOACS ANNO 2017 CLOSING THE GAPS...Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.63 (95%...
Transcript of DOACS ANNO 2017 CLOSING THE GAPS...Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.63 (95%...
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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
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COUMARINE VAN MARC
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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
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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
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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
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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
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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
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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
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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.
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Bafta Study,Lancet,2008.
NOACS FOR STROKE PREVENTION IN >75 ?
NOAC VS. WARFARIN (22371 PATIENTS)HR 0.71 (0.62-0.83)
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Ann Intern Med 2009
Netclinical Benefitby Age
Alexander,JACC,2016
NIERINSUFFICIENTIE?Warfarin
vs.Apixaban
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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
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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
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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
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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
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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