Antitrombotische behandeling van AF en VTEANNO 2018
Professor Saskia Middeldorp, M.D.
Academic Medical Center
Amsterdam, The Netherlands
@MiddeldorpS
Vinkeveen, 25 May 2018
Disclosures Saskia Middeldorp
Research Support and Lecture Fees
• Aspen
• Bayer
• BMS/Pfizer
• Boehringer Ingelheim
• Daichi Sankyo
• GSK
• Portola
• Sanquin
• Sanofi
Outline
1. Anticoagulants for AF – triple, double, single?
2. Anticoagulants for VTE - what we’ve learned in 2017
3. Bleeding on anticoagulants
4. What the future will bring
Anticoagulation in Atrial Fibrillation
Cardiology is simple
Chads2Vasc
DOACs generally preferred over VKA
What to do with ACS?
De Wilde, Lancet 2013
PCI in AF patients
ASA P2Y12 Therapeutic anticoagulation+ +
1 + 1 + 1 > 3~15% major bleeding
WOEST-like regimens using DOACs
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
RE-DUAL-PCI1
Dabi 110/150 mg + P2Y12
PIONEER-AF-PCI2
Riva 15 mg + P2Y12Riva 2.5 bid + DAPT
AUGUSTUSApix 5 mg + P2Y12 (+/-ASA)
ENTRUST-AF-PCIEdox 30/60 mg + P2Y12
1: Cannon, NEJM 2017; 2: Gibson, NEJM 2016
• 6 mos
• 1, 6, 12 mos (doctor’s
discretion)
• 6 mos
• 30 d – 12 mos
Standard is shifting: ESC guideline
Ischemic concerns Bleeding concerns
PIONEER-AF-PCI
26.7%
17.4%
NNT = 11
PIONEER-AF-PCI
Na WOEST, PIONEER, RE-DUAL….
Should we stop using Triple Therapy tomorrow?
March 6, 2017
Attract Trial, 2 years of follow-up
CTD
N=337
Control
N=355
Risk Ratio (95%CI)
PTS at 24 months
Villalta > 5
47% 48% 0.96 (0.82-1.11)
Major Bleeding
10 days
1.7% 0.3% 6.18 (0.78-49.2)
Major Bleeding
2 years
5.7% 3.7% 1.52 (0.76-3.01)
Recurrent VTE 12% 8% 1.47 (0.94-2.29)
Quality of life Comparable
Vedantham S, New Engl J Med December 2017
Ten Cate-Hoek, BMJ Open 2014;
ISTH 2017
The IDEAL DVT Trial
Individualised
duration
compression
stockings
N=432
Standard
duration
compression
stockings
N=424
Odds Ratio
(95%CI)
PTS at 24 months
Villalta > 5 (2 consecutive
visits)
29% 28% 1.06 (0.78-1.44)
PTS at 24 months
Villalta ISTH > 5 (any
visit)
51% 45% 1.24 (0.94-1.64)
Major Bleeding
2 years
5.7% 3.7% 1.52 (0.76-3.01)
Recurrent VTE 8% 8%
Quality of life To be reported
What I will show you
1. The threshold for extended duration of anticoagulanttreatment after a first episode of VTE is rapidlydecreasing
2. DOACs may be an alternative to LMWH in treatment of VTE in cancer patients
3. Future generations of anticoagulants
4. Antidotes for DOACs
1. Risk of recurrent VTE
Can we predict it?
Does it matter - impact on duration of treatment?
Risk of recurrent VTEAfter the acute phase
Prandoni,
Haematologica
2007
Extended treatment
• Acute phase ~ 3 months
• The choice therefore:
- Limited duration
(“3 months is enough”)
- Extended treatment
JAMA, 2015
Long term treatment: 80% risk
reduction of recurrent VTE
Catch-up phenomenon
Unprovoked DVT
3 months
12 months
No difference after 2 years
Longer duration (6 - 24 months)
POSTPONES recurrence
Does NOT PREVENT recurrence
PADIS-PE, JAMA 2015
Recommendations over the years – to the DOAC era
ACCP 7, 2004 At least 6 to 12 months
Consider for indefinite
1A
2A
ACCP 8, 2008 Long-term treatment
if risk factors for bleeding are
absent
1A
ACCP 9, 2012 Low/moderate bleeding risk:
Extended duration
High bleeding risk:
3 months
2B
1B
ESC, 2014 Low bleeding risk:
Extended duration
2A
ACCP 10, 2016 Low/moderate bleeding risk:
Extended duration
High bleeding risk:
3 months
2B
1B
DOAC for Extended VTE Treatment
RECURRENT VTE
+
VTE DEATH
MAJOR
BLEEDING MAJOR + CRNM
BLEEDING
Drug Trial Dose DOAC vs Comparator (%), P-value
ApixabanAMPLIFY-EXT (placebo comparator)
2.5 mg 2ddSuperiority
81% RRR
1.7 vs 8.8
Not significant0.2 vs 0.5
NR*
Not significant3.2 vs 2.7
NR*
5 mg 2ddSuperiority80% RRR1.7 vs 8.8
Not significant0.1 vs 0.5
NR*
Not significant4.3 vs 2.7
NR*
Rivaroxaban
EINSTEIN-Extension (placebo comparator)
20 mg 1ddSuperiority82% RRR1.3 vs 7.1
Not significant0.7 vs 0
Significant increase6.0 vs 1.2
EINSTEIN-Choice
(aspirin comparator)
20 mg 1ddSuperiority66% RRR1.5 vs 4.4
Not significant0.5 vs 0.3
Not significant2.7 vs 1.8
10 mg 1ddSuperiority74% RRR1.2 vs 4.4
Not significant0.4 vs 0.3
Not significant2.0 vs 1.8
Dabigatran
RE-SONATE (placebo comparator)
150 mg 2ddSuperiority92% RRR 0.4 vs 5.6
Not significant0.3 vs 0
Significant increase5.3 vs 1.8
RE-MEDY (warfarin comparator)
150 mg 2ddNon-inferiority
1.8 vs 1.3Not significant
0.9 vs 1.8
Significant reduction46% RRR5.6 vs 10.2
Major bleeding 0 to 0.9%
Major + CRNM 3.2 to 6.0%
Risk of recurrent VTE outweighsbleeding risk
Major bleeding 0 to 0.9%
Major + CRNM 3.2 to 6.0%
EXTENDED TREATMENT WITH LOW DOSEDOAC
Amplify Extension Study
DVT vs PE: 65 vs 35%
Unprovoked: 92%
Previous VTE: 12%
Agnelli, NEJM 2013
EINSTEIN CHOICE Evaluated Rivaroxaban Versus ASA for Extended Treatment of VTE
30-day
follow-up
Rivaroxaban 10 mg od
n=1136
Day 1
ASA 100 mg od
n=1139
12-month planned
treatment duration†
Population: Patients with confirmed symptomatic PE/DVT
who completed 6–12 months’
anticoagulation*
R
N=3396
Objectives: Compare the efficacy and safety of once daily rivaroxaban (20 or 10 mg) with aspirin (100
mg) in VTE patients who completed 6 to 12 months of treatment and with equipoise regarding the
need for extended anticoagulation
Rivaroxaban 20 mg od
n=1121
*Completed 6–12 months anticoagulation at randomization with no interruption of anticoagulation >1 week†Patients randomized after the requisite number of primary efficacy outcomes was reached were treated for ≥6 months
Weitz JI et al, Thromb Hemost 2015;114:645–650;
Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518
Multicentre, randomized, double-blind, active-comparator, event-driven, superiority study
Efficacy and safety
Efficacy*
*Intention-to-treat analysis; #safety analysis; ‡no events after Day 360 up to Day 480
Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518
0
1
2
4
5
3
Days‡
ASA 100 mg od
Rivaroxaban 20 mg odRivaroxaban 10 mg od
1 30 60 90 120 150 180 210 240 270 300 330 360
Cu
mu
lati
ve
in
cid
en
ce
(%
)
Rivaroxaban 20 mg od vs ASA
6/1107 (0.5%) vs 3/1131 (0.3%)
HR=2.01 (95% CI 0.50–8.04), p=0.32
Rivaroxaban 10 mg od vs ASA
5/1127 (0.4%) vs 3/1131 (0.3%)
HR=1.64 (95% CI 0.39–6.84), p=0.50
Major bleeding#
ASA 100 mg od
Rivaroxaban 20 mg od
Rivaroxaban 10 mg od
Days
0
1
2
3
4
5
Cu
mu
lati
ve
in
cid
en
ce
(%
)
1 30 60 90 120 150 180 210 240 270 300 330 367
Rivaroxaban 20 mg od
vs ASA
17/1107 (1.5%) vs
50/1131 (4.4%)
HR=0.34 (95% CI
0.20–0.59), p<0.001Rivaroxaban 10 mg od
vs ASA
13/1127 (1.2%) vs
50/1131 (4.4%)
HR=0.26 (95% CI
0.14–0.47), p<0.001
Efficacy: Subgroups
Rivaroxaban
20 mg od
(n=1107)
Rivaroxaban
10 mg od
(n=1127)
ASA
100 mg od
(n=1131)
Recurrent VTE, all patients, n/N (%) 17/1107 (1.5) 13/1127 (1.2) 50/1131 (4.4)
Risk profile, n/N (%)
Unprovoked index event 8/441 (1.8) 7/480 (1.5) 26/468 (5.6)
Provoked index event 9/666 (1.4) 6/647 (0.9) 24/663 (3.6)
History of previous VTE, n/N (%)
Yes 3/198 (1.5) 2/197 (1.0) 17/194 (8.8)
No 14/909 (1.5) 11/930 (1.2) 33/937 (3.5)
Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518
2. VTE treatment in cancer patients
Are we getting closer to treatment with oral agents?
Thrombosis and cancer: a two-sided association
• 18% of patients with VTE have cancer
Heit, Arch Intern Med 2002
CATCH: recurrent VTE
HR 0.65 (0.41-1.03)
warfarin (TTR 47%): 10.0%
tinzaparin: 6.9%
Lee, JAMA, 2015
LMWH vs VKA: recurrent VTE meta-analysis
RR 0.57 (0.43-0.75)
Van Es, Drugs 2016
LMWH vs VKA: major bleeding meta-analysis
RR 1.08 (0.65-1.79)
Van Es, Drugs 2016
DOACs in VTE treatment for cancer patients?
• Evidence from phase 3 VTE trials with DOACs
Van Es, Blood 2015; Van Es, Thromb Haemost 2015
Hokusai Cancer VTE study
• N=1050
• Non-inferiority design
• Composite outcome of recurrent VTE + major bleeding
Outcomes
Edoxaban
N=522
Dalteparin
N=524
Hazard Ratio (95%CI)
Primary outcome 12.8% 13.5% 0.97 (0.70 to 1.36)
Recurrent VTE 7.9% 11.3% 0.71 (0.48-1.06)
Major bleeding 6.9% 4.0% 1.77 (1.03-3.04)
CRNMB 14.6% 11.1% 1.40 (1.03-1.89)
Event-free
survival at 12
months
55.0% 56.5% 0.93 (0.77-1.11)
Raskob et al, New Engl J Med 2017
Select-D Trial
Study design (1) Prospective, randomised, open-label, multicentre pilot phase III
Rivaroxaban
Study population: Active cancer with symptomatic DVT
and/or any PE ECOG PS < 2
Dalteparin
R
6 months
n=530
Stratification variables: Stage of disease Baseline platelet count Type of VTE Risk of clotting by tumour type
15 mg bid for 21 days followed by 20 mg od
200 IU/kg od for the first 30 days followed by 150 IU/kg od
Young et al, ASH late breaking clinical trial, 2017
Select D
Rivaroxaban
N=203
Dalteparin
N=203
Risk difference
%(95%CI)
Recurrent VTE 4% 11%
Major bleeding 4% 3%
CRNMB 12% 3%
Overall survival at
6 months
75% 70%
Young et al, ASH late breaking clinical trial, 2017
Study design Caravaggio Trial
3. Anticoagulants beyond DOACs
Can we get away without bleeding?
Other targets: factor XI
Buller et al, New Engl J Med 2014
Other targets: factor XI
Prevention of VTE after total knee replacement
Buller et al, New Engl J Med 2014
FXI-ASO
Enoxaparin
40 mg
N=72
FXI-ASO
200 mg
N=144
FXI-ASO
300 mg
N=77
VTE (95% asymptomatic) 30%
(20-43%)
27%
(20-35%)
4% *
(1-12%)
Major and clinically relevant
non-major bleeding
8%
(3-17%)
3%
(1-7%)
3%
(<1-9%)
Buller et al, New Engl J Med 2014
Endogenous fibrinolysis enhancers
• LMW imidazole derivative that inhibits TAFIa (DS-1040)
• Heterodimer diabody against TAFI and PAI-1
• α 2-antiplasmin – inactivating antibody (both circulatingand firbrin bound; TS23; DS-9231)
• PAI-1 inhibitors (PAI trap (H37R)-HSA, and others)
1. J. Zhou et al. JTH, 2017; 2. T. Wyseure et al, Blood 2015; 3. S. Singh et al.
Circulation, 2017; 4. S. Peng et al. TH, 2017
Endogenous fibrinolysis enhancers
Zhou et al. JTH 2017
No effect on coagulations parameters or bleedingtime in healthy subjects
Zhou et al. JTH, 2017
Phase 1b study in patients with PE ongoing
3. STUDY DESIGN
3.1. Overall Design
This will be a randomized, double
ascending dose study in subjects with acute
intermediate- risk or submassive PE
in Figure 3.1.
Figure 3.1: Study Design
3.2. Discussion of Study
This study will follow an adaptive design and
dose/continuous infusion time cohorts, organized in three pairs (1
two dose optimization evaluations
cohorts. Through the interim dose opt
PK/PD and biomarker data) the study aims to also identify a range of DS
that provide close to complete inhibition of TAFI activity and to estimate
duration of administration of such
reductions in total thrombus volume
Protocol DS1040
Version 1.0, 21 Jan 2016
Proprietary and Confidential
Page 31
STUDY DESIGN
Design
ouble-blind, placebo-controlled, multi-center, single
in subjects with acute PE characterized as low-risk or
risk or submassive PE. A graphical representation of the study is provided
Study Design
Discussion of Study Design
This study will follow an adaptive design and include up to six sequential, ascending
dose/continuous infusion time cohorts, organized in three pairs (1-2, 3-4, and 5
two dose optimization evaluations are planned in between the first and second pair of
Through the interim dose optimization evaluations (using modeling of imaging,
PK/PD and biomarker data) the study aims to also identify a range of DS-1040b doses
that provide close to complete inhibition of TAFI activity and to estimate the optimal
duration of administration of such doses in order to achieve clinically meaningful
volume.
DS1040-B-U107
1.0, 21 Jan 2016
ingle-
the study is provided
include up to six sequential, ascending-
4, and 5-6). Up to
in between the first and second pair of
imization evaluations (using modeling of imaging,
1040b doses
the optimal
clinically meaningful
4. Antidotes
Do we need them now that we have them?
Surrogate endpointTo correct INR
Clinical endpoint
To improve outcome
Evidence for antidotes
What we have What we need…
Hemostatic efficacy – The New Benchmark
Effe
ctive/G
oo
dIn
effe
ctive/
Poo
r
30 d Thromboembolism 8%
VKA
Reversal for DOAC in urgent surgeryHow important is this?
Peri-procedural bleeds in RE-LY (dabigatran)
No difference with warfarin despite the absence of a specificantidote
Healey, Circulation 2012
Urgent
surgery
VKA
N=111
Dabigatran
110 mg bid
N=107
Dabigatran
150 mg bid
N=141
% Major bleeds 21.6 17.8 17.7
RR (95%CI) vs
VKA
1 0.82 (0.48-
1.41)
0.82 (0.50-
1.35)
In a bleeding patient, ask the right questions
1. What anticoagulant is prescribed?
2. Is anticoagulant present at high quantity?
• When was last dose taken?
• Half-life and renal function, (age, weight)?
3. Site and severity of bleed?
• Local measures?
• Is reversal necessary?
DOAC antidotaDabigatran: Idarucizumab (Praxbind)
• Humanized antibody
• 300x binding to dabigatran than dabigatran with thrombin
• single bolus of 2 x 2.5 gram i.v.
• Registered in 2015, available in most hospitals now
SPC Praxbind; www.ema.europe.eu
RE-VERSE-AD
Assay upper
limit of normal
Diluted thrombin time
Idarucizumab
2x 2.5 g
dT
T (
s)
130
110
70
60
50
40
30
20
120
100
90
80
1h 2h 4h 12h 24hBaseline Between
vials
10–30
min
Time post idarucizumab
N= 90
Mortality 20%
Acute bleeding n=51
11.4 u until cessation of
bleeding
Acute surgery n=39
92% normalization of
coagulation
Pollack, N Eng J Med 2015/ Full cohort analysis NEJM 2017
DOAC antidotaFactor Xa inhibitors: Andexanet alfa
Catalytic domain
Gla domein
Siegal, N Eng J Med 2015
Andexanet alfa – not yet on the market
Connolly NEJM 2017
Anti-Xaactivitydecrease: 89%(58 – 94%)
Hemostatic Efficacy with Andexanet
• Excellent or good in 79% (95%CI 64-89)
Connolly NEJM 2017
Andexanet alfa – not yet on the market
Siegal NEJM 2015
PCC in rivaroxaban treated healthy volunteers
50 IU/kg 50 IU/kg
Surrogate endpointTo correct INR
Clinical endpoint?????
Factor Xa inhibitor and Prothrombin complex concentrate (PCC)
apixaban
Eerenberg, Circulation 2011Cheung, J Thromb Haemost 2015
DOAC Bleeding RegistryManagement
Into perspective
Xa
inhibitor/PCC
(DOAC
bleeding
registry)
VKA/PCC Dabigatran/
Idarucizumab
Xa inhibitors/
Andexanet alfa
N 32 98 301 (98 ICH) 67
Effective
hemostasis
87%
(70%-95%)
72%
(64% - 81%)
100% *
(97% - 100%)
79%
(65% - 88%)
30d Thrombo-
embolism
3.1%
(0.6% - 15.7%)
7.8%
(4.0% - 14.6%)
6.8%
(3.2% - 7.0%)
18%
(11% - 29%)
Sarode, Circulation 2013; Pollack Jr, N Eng J Med 2017
Connolly, N Eng J Med 2016; Brekelmans RPTH 2017
* ICH not evaluable
Take home!
Anticoagulants in cardiology – striking the right balance
No aggressive treatment for DVT
• NO catheter directed thrombolysis
• NO stockings forever
Indefinite treatment for patients with unprovoked VTE and low bleeding risk is the default
Oral FXa inhibitor in cancer patients with VTE – carefulconsideration in GI cancers – CARAVAGGIO trial ongoing
Antidotes for life threatening bleeding
The future is bright
This is the FUN part, thank you!
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