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

Randomise d Dabigatr an E te xilate Dose F inding Study In Patie nts With Ac ute Cor onar y Syndr ome s Post Inde x E ve nt With Additional Risk F ac tor s F or 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

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 om Boe hr inge r - Inge lhe im

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

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 Dabigatran Dabigatran 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 ow pote ntia l for food/ drug inte ra c tions, not a CYP 450 substra te , inhibitor or induc e r – Active site Active site No c oa g ula tion monitoring re quire d Thrombin Thrombin of thrombin of thrombin – E ffic ac y a nd sa fe ty c ompa ra ble to L MW he pa rin molecule molecule for pr e ve ntion of VT E a fte r or 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)

Obje c tive s Compare treatment with 4 different dose regimens of 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)

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, on aspirin & clopidogrel at randomisation Randomisation within 14 days Placebo Dabigatran Dabigatran Dabigatran b.d 50 mg b.d 75 mg b.d 110 mg b.d Dabigatran N=373 N=372 N=371 N=411 150 mg b.d N=351 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 .

Ba se line c ha ra c te ristic s Number of patients 1878 STEMI / NSTEMI 60 / 40 % PCI at index event Age (mean) 61.8 years 54 % Gender (males) 76 % Days to randomisation 7.4 days (mean) Risk factors for cardiovascular complications: Age ≥ 65 years 44 % Left bundle branch block 3 % Diabetes mellitus 31 % Congestive Heart Failure 12 % Previous MI 29 % GFR 30-60 ml/min 9 % Peripheral artery disease 6 % No revascularisation for 31 % index event

Conc omita nt a ntipla te le t me dic a tion Aspirin only Aspirin+Clopidogrel % 100 90 80 70 60 50 40 30 20 10 0 5 mo 2 wk R 1 mo 2 mo 3 mo 4 mo 6 mo FU EOT R=Randomisation, EOT=End of treatment, FU=Follow-up

Study drug disc ontinua tion Placebo D 50 D 75 D 110 D 150 No of pts 373 372 371 411 351 Serious adverse events 9 % 9 % 8 % 9 % 6 % Discontinued 14 % 20 % 16 % 19 % 18 % study treatment 8 % 9 % 8 % 12 % 10 % - due to AE 0 ,2 0 0 ,1 8 0 ,1 6 0 ,1 4 0 ,1 2 Placebo 0 ,1 0 D50 0 ,0 8 D75 0 ,0 6 D110 0 ,0 4 D150 0 ,0 2 Days 0 ,0 0 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

Prima ry outc ome - de finition Major ble e ding (IST H*) •Fatal bleed and/ o r •Symptomatic bleeding in a critical area or organ , and/ o r •Bleeding causing a fall in hemoglobin level of ≥ 20 g/L, or 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

Prima ry outc ome - ble e ding Clinic a lly re le va nt minor % Ma jor (IST H) 9 P < 0.001 linear trend 8 N=1861 7 6 5 24 23 23 23 4 3 10 15 2 14 9 7 7 1 8 6 4 4 3 2 2 1 1 1 0 IT T OT IT T OT IT T OT IT T OT IT T OT Pla c e bo D 50 D 75 D 110 D 150 ITT = Intention to treat; OT = On treatment (within 3 days before the event)

Prima ry outc ome – Major and c linic ally r e le vant minor ble e ding T ime to first e ve nt 0,09 D150* 0,08 D110* 0,07 0,06 0,05 D75 0,04 D50 0,03 0,02 Placebo 0,01 0 0 20 40 60 80 100 120 140 160 180 Days *p < 0.01 log rank test vs placebo N=1861

Ma jor ble e ding c ompa risons Placebo D 50 D 75 D 110 D 150 N=371 N=369 N=368 N=406 N=347 ISTH Major 0.5 % 0.8 % 0.3 % 2.0 % 1.2 % TIMI Major 0.3 % 0.3 % 0 1.2 % 0.3 % GUSTO Severe 0.3 % 0.3 % 0 0.5 % 0

D- dime r – se c onda ry outc ome (me dia ns)  g/L 175 Placebo D50 150 D75 D110 125 D150 100 75 p < 0.001 50 25 0 4 26 28 Weeks R 1 EOT FU R=Randomisation, EOT=End of treatment, FU=Follow-up

Clinic a l e ndpoint – se c ondar y outc ome c omposite of CV de ath, non fatal MI, str oke % 9 Str oke 8 Non- fatal MI CV de ath 7 N=1861 6 5 1 1 4 3 8 9 8 3 2 8 4 8 8 4 2 7 9 9 8 8 1 4 8 6 4 4 5 2 0 ITT OT ITT OT ITT OT ITT OT ITT OT Placebo D 50 D 75 D 110 D 150 ITT = Intention to treat; OT = On treatment (within 3 days before the event)

Conc lusions Dabigatran in addition to aspirin and clopidogrel after an acute coronary syndrome is associated with a • low overall bleeding rate , with – dose dependent increase in the composite of major (ISTH) and clinically relevant minor bleeding – < 1% absolute increase in major/severe bleeds (ISTH, TIMI, GUSTO) with dabigatran 110 - 150 mg b.d. • significant reduction in coagulation activity (D-dimer) without dose relationship • low number of clinical endpoints in all treatment arms • good tolerability with all four doses

Implic a tions • Dabigatran up to 150 mg b.d. on top of dual antiplatelet therapy can be used with modestly increased bleeding risk – This is of relevance for atrial fibrillation patients after acute coronary syndromes and stenting • RE-DEEM supports the rationale for evaluation of the 110 and 150 mg dabigatran doses on clinical outcome in acute coronary syndrome patients in a larger adequately powered study

Thank You! Denmark Ireland Finland UK Norway Sweden Russia Canada Korea USA Bulgaria Czech Rep Georgia Belgium Hungary France Poland Germany Romania Italy Ukraine India Netherlands Spain First patient in March 14, 2008; Last patient out October 2, 2009