Freek W.A. Verheugt

POSSIBLE ROLE OF RIVAROXABAN IN ACS PATIENTS:

LESSONS LEARNED FROM ATLAS ACS-2 TIMI-51

Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG)

Amsterdam, The Netherlands

received educational and departmental grants

fromBayer AG, Boehringer Ingelheim and Eli Lilly

received speaker fees and honoraria for

consultancy from Sanofi-Aventis, Bayer AG,

Boehringer Ingelheim, Merck and Eli Lilly

Freek W.A. Verheugt

1.

2.

Antiplatelet therapy in ACS: efficacy vs safety

0

5

10

15

20

25

Pa

tien

ts w

ith

eve

nts

(%

)

1. Antiplatelet Trialists' Collaboration, BMJ 1994; 2. Antithrombotic Trialists' Collaboration, BMJ 2002;

3. Wiviott et al. N Engl J Med 2007; 4. Wallentin et al. N Engl J Med 2009

Cardiovascular death, MI, or stroke

Major bleeding

ASA1,2 ASA +

clopidogrel3ASA +

prasugrel3

↓25%

↓20%

↓18%

↑60% ↑38% ↑33%

ASA +

ticagrelor4

↓33%

None

20%0.8%

15% 1.3% 12% 1.8% 10% 2.4% 10% 1.8%

Antiplatelet Agents in PCI for ACS in Sweden 2011

Swedeheart Annual Report 2011

Antiplatelet therapy after ACS, Stroke or PAD: long-term efficacy

CHARISMA. N Engl J Med 2006;354:1706-1717

Thrombus composition in STEMI

Silvain J. J Am Coll Cardiol 2011;57:1359–1367

Secondary Prevention With Warfarin and ASA vs ASA Alone After ACS

10 trials; n = 5938

Death

MI

Ischaemic stroke

Major bleeding event

Minor bleeding event

0.96 (0.77–1.20)

0.56 (0.46–0.69)

0.46 (0.27–0.77)

2.48 (1.67–3.68)

2.65 (2.14–3.29)

Rate ratioWarfarin +ASA better

ASA better

0.05 1.0 5.0

Rate ratio (95% CI)

Rothberg MB. Ann Intern Med 2005;143;241-250.

ESTEEM study: death/MI/stroke

0

2

4

6

8

10

12

14

0 30 60 90 120 150 180

Days after randomization

Cumulative risk (%)

7.4

11.1

Combined ximelagatran vs placebo: HR=0.66 (0.48; 0.90), p=0.0105

Placebo (n=638)

Combined ximelagatran (n=1245)

Lancet 2003;362:789–797

ESTEEM study: Bleeding events

0

5

10

15

20

25

30

Cumulative risk (%)

Placebo 24 mg 36 mg 48 mg 60 mg

Major bleed

0.92.0

0.73.2 1.5 1.8

Total bleed (major + minor)

13.2 18.9 20.1 24.8 23.8 21.9

Combinedximelagatran

Lancet 2003;362:789–797

Apixaban 5 mg BID

CrCl<40 ml/min 2.5 mg BID

Primary Outcome: CV Death, MI, Ischemic Stroke

Safety: TIMI Major Bleeding

Randomize 1:1

Double blind• Aspirin

• Other antiplatelet therapy

N=10,800

Placebo

Recent (≤7days) Acute Coronary Syndrome

(STEMI or NSTE-ACS)

At Least 2 Additional Risk-Factors

APPRAISE-2

N Engl J Med 2011;365:699-708

APPRAISE-2 Efficacy

N Engl J Med 2011;365:699-708

13

APPRAISE-2 Safety

N Engl J Med 2011;365:699-708

N Engl J Med 2012;366:9-19

N Engl J Med 2012;366:9-19

16

THR 03718 AHA Thrombosis DT4 5/10/2013 5:06 PM

17N Engl J Med 2012;366:9-19

THR 03718 AHA Thrombosis DT4 5/10/2013 5:06 PM

18N Engl J Med 2012;366:9-19NNH = 575

THR 03718 AHA Thrombosis DT4 5/10/2013 5:06 PM

19N Engl J Med 2012;366:9-19

trial f/u (m) NOAC placebo NNT

APPRAISE-2 8 0.9 1.3 250

ATLAS-21 13 1.1 1.5 250

stent thrombosis (%/yr)

n

7,392

15,526

RR 95% CI)

0.73 (0.47 - 1.12)*

0.69 (0.51- 0.93)**

STENT THROMBOSIS WITH NOACS AFTER ACS

reported

1 both doses * p = 0.15

** p = 0.02

Verheugt FWA. Eur Heart J 2013. Epub March 12

PlaceboApixaban

ATLAS ACS 2 TIMI-51**

APPRAISE-2*12

Months since Randomization

Primary Efficacy End Point Composite of CV Death, MI or Ischemic Stroke

HR 0.84(0.74-0.96)

**N Engl J Med 2012;366:9-19

*N Engl J Med 2011;365:699-708

Courtesy Paul Armstrong

Apixaban 279 (7.5%)

Placebo 293 (7.9%)

HR 0.95; 95% CI 0.80-1.11;

p=0.509

Courtesy Chris Granger

Apixaban 48 (1.3%)

Placebo 18 (0.5%)

HR 2.59; 95% CI 1.50–4.46; p=0.001

TIMI Major Bleeding

APPRAISE 2 ATLAS 2

Courtesy Chris Granger

REMAINING QUESTION

Why is lower dose rivaroxaban better than a higher dose ?

ATLAS ACS-TIMI 46 – low doses: primary efficacy endpoint

Lancet 2009;374:29–38

PENTUA: primary Endpoint (Day 9)

0

10

20

30

40

50P < 0.05

2.5 4 8 12enox

death, MI, re-ischemia

fondaparinux

30.0

43.5 41.034.8

40.2

1.5 4.5 3.5 2.7 2.1

%

Simoons ML. J Am Coll Cardiol 2004;43:2183-2190

27

Fondaparinux for acute treatment in ACS

Time (days)*Mortality at study end

Cu

mu

lati

ve h

aza

rd*

0.02

0.04

0.06

0.08

0.10

0.12

0 18 36 54 72 90 108 126 144 162 180

UFH/placebo

Fondaparinux

HR 0.88

95% CI 0.79, 0.99

p=0.029

OASIS-6

Enoxaparin

FondaparinuxOASIS-5

HR 0.89

95% CI 0.80, 1.00

p=0.05

0

OASIS-5 Trial Group. N Engl J Med 2006; OASIS-6 Trial Group. JAMA 2006

Death through day 180

ASPECT. Lancet 1994;343:499-503

ASPECT-1: Coumadin after ACS

_____

-------- placebo

coumadin

Eur Heart J 2011;32:2541-2554

TIMI MAJOR NON-CABG BLEEDING/YR IN ACS

new therapy reference

PLATO (ticagrelor)3 2.8%**

δ

+ 0.6%

TRITON (prasugrel)2

ATLAS (rivaroxaban 2.5mg bid)5 0.3%

1.4%

2.2%

0.9%***

1.9%*

+ 0.6%

+ 0.5%

1 N Engl J Med 2001;345:494-502

2 N Engl J Med 2007;357:2001-2015

3 N Engl J Med 2009:361:1045-1057

* p = 0.04

** p = 0.03

***p < 0.001

TRACER (vorapaxar)4 0.4%0.9%*** + 0.5%

4 N Engl J Med 2012:366:20-33

HR

1.25

3.46

1.32

1.85

CURE (clopidogrel)1 2.7%3.7%*** + 1.0% 1.38

5 N Engl J Med 2012:366:9-19

ESTIMATED NUMBER NEEDED TO HARM (NNH) AND

NEEDED TO TREAT (NNT) IN ACS TRIALS

ICH fatal

ICH

PLATO (ticagrelor) 775

TRITON (prasugrel)

ATLAS (rivaroxaban 2.5mg bid) -

?

922

575

-

1 per year

TIMI major

non-CABG1

fatal

bleed

214

-

450

-

214

350

NNT

-

71**

56**

** p < 0.001

NNH

to save

1 life

TRACER (vorapaxar) 920230921107 -

in l

ieu

of

clo

pi

on

to

p o

f D

AP

T

CURE (clopidogrel) ??-100 -

Take home messages

ATLAS ACS-2 TIMI 51 opens a new venue in post ACS treatment

1.

2.

3.

4.

For each 10 lifes saved by rivaroxaban there are 4excess non-CABG TIMI major bleeds and 1 ICH

In balancing benefit and risk dosing withanticoagulation is crucial in ACS and thereafter

Very low dose rivaroxaban on top of DAPT lowersmortality after ACS (to a larger extent thanticagrelor at a no excess risk of fatal ICH)