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!