[PPT] - RE - DE E M J Oldg re n, A Buda j, CB Gra ng e r, R Ha rpe r, Y PowerPoint Presentation

SLIDE 1

Randomise d Dabigatr an E te xilate Dose F inding Study In Patie nts With Ac ute Cor

nar

y Syndr

me s Post Inde x

E ve nt With Additional Risk F ac tor s F

r

Car diovasc ular Complic ations Also Re c e iving Aspir in and Clopidogr e l

RE

DE

E M

J Oldg re n, A Buda j, CB Gra ng e r, R Ha rpe r, Y Khde r, F va n de We rf, L Wa lle ntin, for the RE

DE

E M inve stig a tors

SLIDE 2

Disc losure

Jonas Oldgren MD, PhD Randomised Dabigatran Etexilate Dose Finding Study In Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors For Cardiovascular Complications Also Receiving Aspirin And Clopidogrel (RE-DEEM)

F inanc ial disc losur e : Na tiona l Advisor y Boa r d & Re se a r c h Gr ant fr

m Boe hr

inge r

Inge lhe im

SLIDE 3

Ba c kg round

After acute coronary syndromes patients continue to

have recurrent ischemic events despite revascularization and dual antiplatelet therapy

Oral anticoagulation is superior to aspirin alone following

acute coronary syndromes, however warfarin is rarely used

Novel oral anticoagulants offer an opportunity to reduce

recurrent ischemic events beyond dual antiplatelet therapy but also pose a risk of bleeding, as shown in previous phase II studies with inhibitors of factors IIa and Xa

SLIDE 4

Da big a tra n e te xila te

a n ora l dire c t thrombin inhibitor

–

Ra pid ora l a bsor ption & biotr a nsfor ma tion of prodrug to a c tive drug

–

Bioa va ila bility 6.5%

–

Ra pid onse t, T ½ ~ 14- 17 h

–

Ma inly re na l e xc re tion (80% )

–

L

w pote ntia l for food/ drug inte ra c tions, not a

CYP 450 substra te , inhibitor or induc e r

–

No c oa g ula tion monitoring re quire d

–

E ffic ac y a nd sa fe ty c ompa ra ble to L MW he pa rin for pr e ve ntion of VT E a fte r

r

thope dic sur ge r y

–

Be tte r e ffic a c y a nd sa fe ty tha n wa rfa rin for stroke pre ve ntion in a tria l fibrilla tion (RE

L

Y)

Dabigatran Dabigatran Thrombin Thrombin

Active site Active site

f thrombin
f thrombin

molecule molecule

SLIDE 5

Obje c tive s

Compare treatment with 4 different dose regimens

f dabigatran versus placebo for 6 months in

patients on dual antiplatelet treatment after acute coronary syndrome concerning

major & clinical relevant minor bleeding events

(primary outcome)

levels of coagulation activity, i.e. D-dimer

(secondary)

composite of cardiovascular death, non-fatal MI

and non-hemorrhagic stroke (secondary)

SLIDE 6

Phase II RE-DEEM Overview

Randomised, double blind, placebo controlled, dose escalation study

ST elevation or non-ST elevation ACS with ≥ 1 additional risk factor for CV complications,

n aspirin & clopidogrel at randomisation

Placebo b.d N=373 Dabigatran 50 mg b.d N=372 Dabigatran 75 mg b.d N=371 Dabigatran 110 mg b.d N=411 Dabigatran

150 mg b.d

N=351

Randomisation within 14 days

Study treatment for 6 months

Dose a djustme nts: Pa tie nts with mode ra te re na l impa irme nt (GF R 30- 50 ml/ min) ra ndomise d to 75, 110 or 150 mg we re a na lyse d a s pa rt of tha t dose g roup but we r e tr e ate d with the ne xt lowe r dose .

SLIDE 7

Ba se line c ha ra c te ristic s

1878

Number of patients

76 %

Gender (males)

61.8 years

Age (mean)

44 %

Age ≥ 65 years

6 %

Peripheral artery disease

29 %

Previous MI

31 %

Diabetes mellitus

60 / 40 %

STEMI / NSTEMI

54 %

PCI at index event

7.4 days

Days to randomisation (mean)

Risk factors for cardiovascular complications: 31 %

No revascularisation for index event

9 %

GFR 30-60 ml/min

12 %

Congestive Heart Failure

3 %

Left bundle branch block

SLIDE 8

Conc omita nt a ntipla te le t me dic a tion

Aspirin+Clopidogrel Aspirin only

R=Randomisation, EOT=End of treatment, FU=Follow-up

6 mo EOT 2 wk FU R 1 mo 3 mo 10 20 30 40 50 60 70 80 90 100 % 2 mo 4 mo 5 mo

SLIDE 9

Study drug disc ontinua tion

D 150 D 110 D 75 D 50 Placebo 351 411 371 372 373 No of pts 6 % 9 % 8 % 9 % 9 % Serious adverse events 10 % 12 % 8 % 9 % 8 %

due to AE

18 % 19 % 16 % 20 % 14 % Discontinued study treatment

0 ,0 0 0 ,0 2 0 ,0 4 0 ,0 6 0 ,0 8 0 ,1 0 0 ,1 2 0 ,1 4 0 ,1 6 0 ,1 8 0 ,2 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0

Placebo D50 D75 D110 D150

Days

SLIDE 10

Prima ry outc ome - de finition

Major ble e ding (IST H*)

Fatal bleed

and/

r
Symptomatic bleeding in a critical area or organ,

and/

r
Bleeding causing a fall in hemoglobin level of ≥ 20 g/L,
r leading to transfusion of ≥ 2 units of whole blood or red cells

Clinic ally r e le vant minor ble e ding

A clinically overt bleed that does not meet the criteria

for major bleed but prompts a clinical response,

i.e hospital admission for bleeding, medical or surgical treatment, or a change in antithrombotic therapy including study drug

*International Society of Thrombosis and Haemostasis

SLIDE 11

Prima ry outc ome - ble e ding

ITT = Intention to treat; OT = On treatment (within 3 days before the event)

P < 0.001 linear trend N=1861

%

1 2 3 4 5 6 7 8 9

Ma jor (IST H) Clinic a lly re le va nt minor

Pla c e bo D 50 D 75 D 110 D 150

IT T OT IT T OT IT T OT IT T OT IT T OT

7 2 10 3 15 1 24 8 7 1 9 2 14 1 23 6 23 4 23 4

SLIDE 12

Prima ry outc ome – Major

and c linic ally r e le vant minor ble e ding

T ime to first e ve nt

*p < 0.01 log rank test vs placebo N=1861

0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08 0,09 20 40 60 80 100 120 140 160 180 Days

Placebo D50 D75 D110* D150*

SLIDE 13

Ma jor ble e ding c ompa risons

0.5 % 0.3 % 0.3 % GUSTO Severe 0.3 % 1.2 % 0.3 % 0.3 % TIMI Major 1.2 % 2.0 % 0.3 % 0.8 % 0.5 % ISTH Major Placebo

N=371

D 50

N=369

D 75

N=368

D 110

N=406

D 150

N=347

SLIDE 14

D- dime r – se c onda ry outc ome

(me dia ns)

28 Weeks FU 26 EOT R=Randomisation, EOT=End of treatment, FU=Follow-up 1 4

g/L 25 50 75 100 125 150 175

R

Placebo D50 D75 D110 D150

p < 0.001

SLIDE 15

Clinic a l e ndpoint – se c ondar

y outc ome

c omposite of CV de ath, non fatal MI, str

ke