possible role of rivaroxaban in acs patients learned …summitmd.com/pdf/pdf/25_freek w.a....
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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)