MANAGING ATHERO-THROMBOTIC RISK Early impact and long-term
benefit of antiplatelet therapy
What is the optimal duration What is the optimal duration of antiplatelet therapy?of antiplatelet therapy?
Giuseppe Biondi Zoccai, M.D.Division of Cardiology, University of Turin, Turin, Italy
EFIM-7, Rome, 7-10 May 2008 www.metcardio.org
Disclosure
Within the past 5 years, the presenter or his partner have had a financial interest/arrangement or affiliation with the organizations listed below:
Company Name: Relationship:
Boston Scientific Consultant
Bristol Myers Squibb Speaker bureau
Cephalon Consultant/Speaker bureau
Cordis Speaker bureau
Invatec Consultant
Mediolanum Cardio Research Consultant/Speaker bureau
Introduction:
sample case studies
Case study 1
• 67-year-old man admitted for unstable angina, known for diabetes and symptomatic peripheral artery disease. Coronary angiography showed multivessel disease, subsequently treated with bypass surgery
Case study 1
• In such a patient, provided that he is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last:
A. 1 month
B. 6 months
C. 9 months
D. 12 months
E. 24 months
Case study 2
• 71-year-old woman with stable angina, known for previous ischemic stroke; coronary angiography showed right coronary artery disease treated with percutaneous paclitaxel-eluting stent implantation
Case study 2
• In such a patient, provided that she is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last:
A. 1 month
B. 6 months
C. 12 months
D. 24 months
E. 36 months
Learning goals of this presentation
• What is the evidence supporting dual antiplatelet therapy for 12 months?
• What is the rationale in favor of dual antiplatelet therapy for more than 12 months?
• Is there any risk of late thrombosis with drug-eluting stents?
• What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?
Learning goals of this presentation
• What is the evidence supporting dual antiplatelet therapy for 12 months?
• What is the rationale in favor of dual antiplatelet therapy for more than 12 months?
• Is there any risk of late thrombosis with drug-eluting stents?
• What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?
CURE – primary end point of MI/stroke/CV death (N=12,562)
CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
The primary outcome occurred in 9.3% of
patients in the clopidogrel + ASA
group and 11.4% in the placebo + ASA group
Months of Follow-upMonths of Follow-up
Clopidogrel + ASA
3 6 9
Placebo + ASA
0 12
Cu
mu
lati
ve H
azar
d R
ate
Cu
mu
lati
ve H
azar
d R
ate
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
20%20%Relative Relative
Risk ReductionRisk Reduction P=0.00009
Study subjects had ACS (UA/non–ST-elevation MI)
CREDO – 1-year primary outcome
27%Relative RiskReduction
Months
30 6 9 12
0
5
15
10
De
ath
, MI,
or
Str
ok
e, %
P=.02
8.5%
11.5%
Clopidogreln=1053
Placebon=1063
Adapted from Steinhubl SR, et al. JAMA. 2002;288:2411-2420.
CURE safety
Bleeding ResultsClopidogrel + Aspirin(+ standard therapy*)
N=6,259
Placebo + Aspirin (+ standard therapy*)
N=6,303
Major Bleeding† 3.7% 2.7%
Life-threatening‡ 2.2% 1.8%Fatal 0.2% 0.2%5 g/dL hemoglobin drop 0.9% 0.9%Requiring surgical intervention
0.7% 0.7%
Hemorrhagic strokes 0.1% 0.1%Requiring transfusion (≥4 units)
1.2% 1.0%
Other Major Bleeding§ 1.6% 1.0%Significantly disabling 0.4% 0.3%Intraocular bleeding with significant loss of vision
0.05% 0.03%
Requiring 2–3 units of blood
1.3% 0.9%
Minor Bleeding|| 5.1% 2.4%
† P=0.001. ‡ P=NS.
§ P=0.005.|| P<0.001.
CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Learning goals of this presentation
• What is the evidence supporting dual antiplatelet therapy for 12 months?
• What is the rationale in favor of dual antiplatelet therapy for more than 12 months?
• Is there any risk of late thrombosis with drug-eluting stents?
• What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?
~ 1/4 of the 40,258 patients with CAD also have atherothrombotic disease in other arterial territories
REACH – 1/4 of patients with CAD also have polyvascular disease
CAD
PAD4.7%
8.4%
1.6% CVD16.6%
44.6%
(%s are of total population, n=67,888)
Patients with CAD = 59.3% of
the REACH Registry
population
CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease
4.7%
Multiple risk factors only population
Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295:180–189.
REACH – pts with CAD + PAD have ↑ event rates than those with PAD or CAD alone
1-ye
ar e
ven
t ra
te (
%)
*TIA, UA, other ischaemic arterial event including worsening of PADRates adjusted for age and sexCAD, coronary artery disease; MI, myocardial infarction; REACH, Reduction of Atherothrombosis for Continued Health; TIA, transient ischaemic attack; UA unstable angina
Steg PG et al. JAMA 2007;297:1197–1206.
1.6 1.4 0.9
3.6
13.0
1.4 1.0 0.8
3.1
17.4
3.21.5 1.2
5.5
23.1
0
5
10
15
20
25
CV death Non-fatal MI Non-fatal stroke CV death, MI orstroke
CV death, MI,stroke or
hospitalisation*
CAD alone (n=28,867)PAD alone (n=3,246)
CAD + PAD (n=3,264)
Benefit of clopidogrel amplified in patients with polyvascular disease – CREDO subgroup analysis
Adapted from Mukherjee D et al. Heart 2006;92:49–51.
2116 patients with planned PCI
TVR, target vessel revascularisation
Rel
ativ
e ri
sk r
edu
ctio
n w
ith
cl
op
ido
gre
l (%
)
CHARISMA overall population – primary efficacy outcome (MI, stroke, or CV death)*
* First occurrence of MI, stroke (of any cause), or cardiovascular death.† All patients received ASA 75-162 mg/day.‡ The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary
efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo)
Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.
Cu
mu
lati
ve e
ven
t ra
te (
%)
0
2
4
6
8
Months since randomization‡
0 6 12 18 24 30
Placebo + ASA†
7.3%
Clopidogrel + ASA†
6.8%
RRR: 7.1% [95% CI: -4.5%, 17.5%]P=0.22
CHARISMA primary end point (MI/stroke/CV death) in pts with previous MI, stroke or PAD*
RRR: 17.1 % [95% CI: 4.4%, 28.1%]P=0.01
Pri
mar
y o
utc
om
e ev
ent
rate
(%
)
0
2
4
6
8
10
Months since randomization
0 6 12 18 24 30
Clopidogrel + ASA7.3%
Placebo + ASA 8.8%
N=9,478
Bhatt DL, et al. J Am Coll Cardiol 2007;49:1982–8
* Post hoc analysis
CHARISMA overall population – safety results
Clopidogrel Clopidogrel PlaceboPlacebo
+ ASA+ ASA + ASA+ ASASafety Outcome* - N (%) Safety Outcome* - N (%) (n=7,802) (n=7,802) (n=7,801) (n=7,801)
PP--valuevalue
GUSTO Severe Bleeding 130 (1.7) 104 (1.3)0.09
Fatal Bleeding 26 (0.3) 17 (0.2)0.17
Primary ICH 26 (0.3) 27 (0.3)0.89
GUSTO Moderate Bleeding 164 (2.1) 101 (1.3)<0.001
ICH=Intracranial hemorrhage. • Adjudicated outcomes by intention to treat analysis.
Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.
There was one documented nonfatal case of thrombotic thrombocytopenic purpura among the clopidogrel-treated patients; this patient died one month later from end-stage chronic obstructive pulmonary disease.
Primary End Point▪ First occurrence of ischemic
stroke, MI, or vascular death
Primary End Point▪ First occurrence of ischemic
stroke, MI, or vascular death
Follow-up 1 to 3 yearsFollow-up 1 to 3 years
N=19,185
n=9,586Aspirin 325 mgAspirin 325 mg
n=9,599Clopidogrel 75 mgClopidogrel 75 mg
384 centers 16 countries
384 centers 16 countries
Patient Population▪ Patients with recent MI,
recent ischemic stroke, or established PAD
Patient Population▪ Patients with recent MI,
recent ischemic stroke, or established PAD
CAPRIE - design
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
CAPRIE - efficacy of clopidogrel in MI, ischemic stroke, or vascular death (N=19,185)
Months of Follow-Up
Cu
mu
lati
ve
Eve
nt
Rat
e (%
)
0
4
8
12
16
Clopidogrel
Aspirin Overall Relative Risk
Reduction
8.7%*
0 3 6 9 12 15 18 21 24 27 30 33 36
Aspirin
Clopidogrel
P=0.045
• ITT analysis.
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
Median Follow-up=1.91 years
Study subjects had either recent MI, recent ischemic
stroke, or established peripheral arterial
disease.
CAPRIE post hoc analysis - benefit enhanced in pts with previous ischemic events*
* Self-reported history of IS or MI.ARR=absolute risk reduction; RRR=relative risk reduction; NNT=number needed to treat; IS=ischemic stroke; MI=myocardial infarction; VD=vascular disease.
Ringleb PA et al for the CAPRIE Investigators. Stroke. 2004;35:528-532.
The absolute risk reduction (ARR) among patients with a history of acute events favored the clopidogrel group through the duration of the trial
RRR 14.9%(95% CI 0.3-27.3)
NNT 29ARR 3.4%
IS, MI, rehospitalization
RRR 12.0%(95% CI 0.6-22.1)
NNT 26ARR 3.9%
IS, MI, VD
Learning goals of this presentation
• What is the evidence supporting dual antiplatelet therapy for 12 months?
• What is the rationale in favor of dual antiplatelet therapy for more than 12 months?
• Is there any risk of late thrombosis with drug-eluting stents?
• What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?
Rotterdam-Bern Registry – long-term incidence of DES thrombosis
Daemen J et al. Lancet 2007;369:667–78
8146 patients treated with DES (sirolimus or paclitaxel-eluting stents) followed for a mean of 1.7 years (up to 3)
Stent thrombosis:•Cumulative incidence -> 2.9% rate•Late thrombosis -> costant 0.6% yearly rate
0.6% per year
Duke Registry – clopidogrel and long-term outcomes after DES implantation
En
dp
oin
t (
%)
• Adjusted outcomes were analyzed at 24 months
• Patients in the DES with clopidogrel group had significantly lower rates of death or MI than did patients inthe DES without clopidogrel group
• Among BMS patients, there were no differences in deathor MI
Adjusted rates of death or MI starting at 6 months
Difference = -4.1 ± 3.5
p=0.02
Difference = -0.5 ± 2.7
p=0.70
Eisenstein EL et al. JAMA 2007;297:159–68
Learning goals of this presentation
• What is the evidence supporting dual antiplatelet therapy for 12 months?
• What is the rationale in favor of dual antiplatelet therapy for more than 12 months?
• Is there any risk of late thrombosis with drug-eluting stents?
• What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?
ESC NSTE-ACS guidelines2007 update
Bassand J-P et al. Eur Heart J 2007;28:1598–1660.
• Aspirin is recommended for all patients presenting with NSTE-ACS without contraindication at an initial loading dose of 160 - 325mg (non-enteric) (I-A), and at a maintenance dose of 75 to 100mg long-term (I-A)
• For all patients immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A)
• For all patients with contraindication to aspirin, clopidogrel should be given instead (I-B)
28
NSTE-ACS - recommendations for oral antiplatelet drugs (2007)
Bassand J-P et al. Eur Heart J 2007;28:1598–1660.
ESC PCI 2005 guidelines
Silber S et al. Eur Heart J 2005;26:804-47.
• Aspirin is recommended for all patients undergoing PCI (I-A)
• For all stable patients clopidogrel is recommended after bare-metal stents for 1 month (I-A), drug-eluting stents for 6–12 months and brachytherapy for 12 months or (I-C)
• For patients with NSTE-ACS clopidogrel is recommended for 9–12 months (I-B)
PCI - recommendations for oral antiplatelet drugs (2005)
Silber S et al. Eur Heart J 2005;26:804-47.
International updates
King SB III et al. Circulation 2008;117:261-95.
• For all patients receiving a DES, clopidogrel 75 mg daily should be given for >12 months if patients are not at high risk of bleeding (I-B)
• For those receiving a BMS, clopidogrel should be given for >1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for >2 weeks) (I-B)
• Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement (IIb-C)
International updates – US PCI guidelines (2007)
King SB III et al. Circulation 2008;117:261-95.
Take home messages
Take home messages
• The benefit of dual antiplatelet therapy for 12 months following NSTE-ACS is well established in patients without excessive bleeding risk
• Most recent data and guidelines support dual antiplatelet therapy for 12 months in subjects treated with DES without high bleeding risk
• Given the long-term increased risk of thrombotic events among patients with polyvascular disease or treated with DES, dual antiplatelet therapy beyond 12 months can be considered on a case by case basis in this setting
Conclusions:
sample case studies
Case study 1
• 67-year-old man admitted for unstable angina, known for diabetes and symptomatic peripheral artery disease. Coronary angiography showed multivessel disease, subsequently treated with bypass surgery
Case study 1
• In such a patient, provided that he is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last:
A. 1 month
B. 6 months
C. 9 months
D. 12 months
E. 24 months
Case study 2
• 71-year-old woman with stable angina, known for previous ischemic stroke; coronary angiography showed right coronary artery disease treated with percutaneous paclitaxel-eluting stent implantation
Case study 2
• In such a patient, provided that she is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last:
A. 1 month
B. 6 months
C. 12 months
D. 24 months
E. 36 months
Many thanks
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