Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I...

Neue Konzepte der Therapie venöser Thromboembolien

Paul KyrleUniv. Klinik f. Innere Medizin I

AKH/Medizinische Universität Wien

Therapie der VTE – verschiedene Möglichkeiten

Thrombolyse- hämodynamisch instabile PE, 4-Etagen tVT (?)

UFH- Niereninsuffizienz, hohes Blutungsrisiko

- Cave: HIT II (~ 2 %)

Fondaparinux NMH

Therapie der VTE mit NMH/VKA

gewichtsadaptiert („therapeutische Dosis“) 1 x oder 2 x tgl. s.c. mindestens 5 Tage bis INR mindestens 24 Stunden > 2

VKA ab Tag 1, mindestens 3 Monate (INR 2-3)

Treatment of VTE: past, present and future

Heparin Vitamin K antagonists

Heparin Dabigatran/Edoxaban

Rivaroxaban/Apixaban

Treatment of VTE

acute subacute extended

up to 2 weeks up to 3 - 6 months > 6 months

Idraparinux vs. Heparin/VKA – van Gogh-PE

The van Gogh Investigators. N Engl J Med 2007;357:1094-1104

E R

Initial parenteraltherapy

Single-dummyperiod

Double-dummy period

6 monthsEnd of treatment

Until INR 2.0

Warfarin Warfarin(INR 2.0–3.0)

Dabigatran placebo

Warfarin placebo

DabigatranWarfarinplacebo

E= enrolmentR= randomization

LMWH/Dabigatran vs. LMWH/VKA for acute VTE

Schulman, N Engl J Med 2009

RE-COVER


Recurrent VTE and related death

RE-COVER - Dabigatran for acute/subacute VTE

Non-inferiority p<0.001

RE-COVER - Dabigatran for acute/subacute VTE


Bleeding

EINSTEIN: Rivaroxaban for acute VTE

15 mg bid

Objectively confirmed

DVT without symptomatic

PEN=~2,900

Rivaroxaban

Day 1 Day 21

Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by

VKA to start ≤48 hours, target INR 2.5 (INR range 2–3)

Objectively confirmed PE

with or without symptomatic

DVT

EINSTEIN DVT/PETreatment period of 3, 6 or 12 months

20 mg od

N=~3,300

30

-da

y o

bs

erv

ati

on

p

eri

od

Rivaroxaban

R

Randomized, open-label, event-driven, non-inferiority study

EINSTEIN-DVT - Rivaroxaban for acute DVT

EINSTEIN Investigators, N Engl J Med 2010

Recurrent VTE and related death

HR=0.68 (95% CI: 0.44–1.04)

p<0.001 for non-inferiority

p=0.08 for superiority

Clinically significant bleeding



EINSTEIN-PE

Büller et a., NEJM 2012

Treatment of VTE

acute subacute extended

up to 2 weeks up to 3 - 6 months > 6 months

NOACS as safe and effective

NOACS as effective, but safer

Transient risk factors

Annualized event rate/pt-year (95% CI)

Any transient RF 3.3% (2.8 – 3.9)

Surgery 0.7% (0 – 1.5)

Nonsurgical RF 4.2% (2.8 – 5.6)

Iorio, Arch Intern Med 2012 (systematic review of 15 studies)

Paul Kyrle

Risk of recurrence after unprovoked VTE

Kyrle, Rosendaal & Eichinger, Lancet 2010

Years after Discontinuation of Anticoagulation

Cum

ula

tive

Pro

babi

lity

of R

ecur

renc

e (%

) p < 0,001distal DVT

proximal DVT

symptomatic PE +/- DVT

RR (95% CI): distal 1 proximal 2,5 (1,6 – 3,9) PE 2,4 (1,5 – 3,7)

n = 151

n = 347

n = 333

Rezidivrisiko der VTE

Antikoagulation

- VKA

- NOAK Aspirin Therapie nach Risikostratifitierung

Confirmed symptomatic DVT or PE completing 6 or 12 months of

rivaroxaban or VKA in EINSTEIN VTE

program

Rivaroxaban 20 mg od

PlaceboDay 1

R

N=1,197

Treatment period of 6 or 12 months

30-d

ay o

bse

rvat

ion

al p

erio

d

Confirmed symptomatic DVT or PE completing

6 or 12 months of VKA

~53%

~47%

Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study

EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE

Study design

EINSTEIN Investigators, NEJM 2011

Continued treatment



Continued treatment



4 major bleeds

no major bleeds

AMPLIFY - Extended

Agnelli, NEJM 2012

RE-MEDY™ study design

S, screening; R, randomization.

*Original protocol, 3–6 months of pre-treatment, then 18 months on study drug; amendment allowed 3–12 months of pre-treatment, then up to 36 months on study drug.

ConfirmedVTE

Anticoagulant

therapy

3–12 months*

S R

0–7 days until

INR ≤2.3

Screening/baseline

Dabigatran etexilate 150 mg bid

Warfarin placebo

Warfarin (INR 2.0–3.0)

Dabigatran placebo

Up to 36 months*End of treatment

Follow up 30 daysTreatment period

and “increasedrisk of

recurrence”

Time to first VTE or VTE-related death

Risk of first onset of any bleeding

0

0,5

1

1,5

2

2,5

3

Dabigatran 150 mg bid Warfarin13/1430

Major bleeding

0.9%

1.8%

HR 0.52 (95% CI: 0.27–1.02)

25/1426

Per

cen

tag

e

p = 0.058

On treatment

48% RRR

RRR, relative risk reduction.

RESONATE


Antikoagulation

- VKA


WARFASA

ASPIRE

WARFASA + ASPIRE


Antikoagulation

- VKA


Prediction rules for recurrent VTE

• Men continue and HER DOO2 • Vienna Prediction Model

• DASH Score

• Ottawa Score (cancer patients only)

Preselection of risk factors

• 929 patients with first unprovoked VTE

• impact on the recurrence risk independently confirmed

• simple assessment, reproducibility• clinical variables: age at venous thrombosis, sex,

location, BMI• laboratory variables: FV Leiden, prothrombin

mutation, D-Dimer

Eichinger, Circulation 2010

Vienna Prediction Model

RFs after forward selection

• sex• location (distal vs. proximal vs. PE)• D-Dimer 3 weeks after cessation of

anticoagulation

Eichinger, Circulation 2010


http:/www.meduniwien.ac.at/user/georg.heinze/zipfile/

Circulation 2010;121:1630-1636 data supplement (free access)

Risk calculator


Nomogram to predict recurrence: Vienna Prediction Model

Externe Validierung des VPM

Marcucci et al., ISTH 2013 Multizenterstudie Österreich (first patient in:

Jänner 2013)

Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I...

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