Transcript Document

MANAGING ATHEROTHROMBOTIC RISK
Early impact and long-term
benefit of antiplatelet therapy
What is the optimal duration
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.
B.
C.
D.
E.
1 month
6 months
9 months
12 months
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.
B.
C.
D.
E.
1 month
6 months
12 months
24 months
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)
0.14
Placebo
+ ASA
Cumulative Hazard Rate
0.12
20%
Relative
Risk Reduction
P=0.00009
0.10
Clopidogrel
+ ASA
0.08
Study subjects had ACS
(UA/non–ST-elevation MI)
0.06
The primary outcome
occurred in 9.3% of
patients in the
clopidogrel + ASA
group and 11.4% in the
placebo + ASA group
0.04
0.02
0.00
0
3
6
9
12
Months of Follow-up
CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CREDO – 1-year primary outcome
Death, MI, or Stroke, %
15
Placebo
n=1063
11.5%
27%
Relative Risk
Reduction
10
Clopidogrel
n=1053
5
8.5%
P=.02
0
0
3
6
9
Months
Adapted from Steinhubl SR, et al. JAMA. 2002;288:2411-2420.
12
CURE safety
Bleeding Results
Major Bleeding†
Life-threatening‡
Fatal
5 g/dL hemoglobin drop
Requiring surgical
intervention
Hemorrhagic strokes
Requiring transfusion
(≥4 units)
Other Major Bleeding§
Significantly disabling
Intraocular bleeding with
significant loss of vision
Requiring 2–3 units of
blood
Minor Bleeding||
Clopidogrel + Aspirin
(+ standard therapy*)
Placebo + Aspirin
(+ standard therapy*)
N=6,259
N=6,303
3.7%
2.2%
0.2%
0.9%
0.7%
2.7%
1.8%
0.2%
0.9%
0.7%
†
P=0.001.
P=NS.
§ P=0.005.
|| P<0.001.
‡
0.1%
1.2%
0.1%
1.0%
1.6%
0.4%
0.05%
1.0%
0.3%
0.03%
1.3%
0.9%
5.1%
2.4%
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?
REACH – 1/4 of patients with CAD
also have polyvascular disease
~ 1/4 of the 40,258 patients with CAD also have atherothrombotic
disease in other arterial territories
(%s are of total population, n=67,888)
Patients with
CAD = 59.3% of
the REACH
Registry
population
Multiple risk
factors only
population
CAD
44.6%
8.4%
1.6%
4.7%
CVD
16.6%
PAD
4.7%
CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease
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-year event rate (%)
25
23.1
CAD alone (n=28,867)
PAD alone (n=3,246)
CAD + PAD (n=3,264)
20
15
17.4
13.0
10
5.5
5
1.6 1.4
3.2
3.6 3.1
1.4 1.0 1.5
0.9 0.8 1.2
0
CV death
Non-fatal MI
Non-fatal stroke
CV death, MI or
stroke
CV death, MI,
stroke or
hospitalisation*
*TIA, UA, other ischaemic arterial event including worsening of PAD
Rates adjusted for age and sex
CAD, 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.
Benefit of clopidogrel amplified in patients with
polyvascular disease – CREDO subgroup analysis
2116 patients with planned PCI
Relative risk reduction with
clopidogrel (%)
100
CAD alone (n=1844)
80
Polyvascular disease (n=272)
60
52.2
47.9
45.5
39.1
40
20
15.3
13.6
18.2
0.3
0
Death/ MI
Death/ MI/ TVR
Death/ MI/
urgent TVR
TVR, target vessel revascularisation
Adapted from Mukherjee D et al. Heart 2006;92:49–51.
Death/ MI/
stroke
CHARISMA overall population – primary
efficacy outcome (MI, stroke, or CV death)*
Placebo + ASA†
7.3%
Cumulative event rate (%)
8
Clopidogrel + ASA†
6.8%
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
P=0.22
2
0
0
6
12
18
24
30
Months since randomization‡
* 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.
CHARISMA primary end point (MI/stroke/CV
death) in pts with previous MI, stroke or PAD*
Primary outcome event rate (%)
10
N=9,478
Placebo + ASA
8.8%
8
Clopidogrel + ASA
7.3%
6
4
RRR: 17.1 % [95% CI: 4.4%, 28.1%]
P=0.01
2
* Post hoc analysis
0
0
6
12
18
24
30
Months since randomization
Bhatt DL, et al. J Am Coll Cardiol 2007;49:1982–8
CHARISMA overall population –
safety results
Safety Outcome* - N (%)
GUSTO Severe Bleeding
Clopidogrel Placebo
+ ASA
+ ASA
(n=7,802) (n=7,801)
P-value
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
164 (2.1)
101 (1.3)
<0.001
GUSTO Moderate Bleeding
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.
ICH=Intracranial hemorrhage.
• Adjudicated outcomes by intention to treat analysis.
Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.
CAPRIE - design
N=19,185
n=9,599
Patient Population
▪ Patients with recent MI,
recent ischemic stroke,
or established PAD
n=9,586
Clopidogrel 75 mg
Aspirin 325 mg
Follow-up 1 to 3 years
Primary End Point
▪ First occurrence of ischemic
stroke, MI, or vascular death
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
384 centers 16
countries
CAPRIE - efficacy of clopidogrel in MI,
ischemic stroke, or vascular death (N=19,185)
Median Follow-up=1.91 years
Aspirin
Cumulative
Event Rate (%)
16
8.7%*
Overall
Relative Risk
Reduction
Clopidogrel
12
Aspirin
P=0.045
8
Clopidogrel
Study subjects had
either recent MI,
recent ischemic
stroke, or established
peripheral arterial
disease.
4
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Months of Follow-Up
•
ITT analysis.
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
CAPRIE post hoc analysis - benefit enhanced
in pts with previous ischemic events*
The absolute risk reduction (ARR) among patients with a history of acute
events favored the clopidogrel group through the duration of the trial
RRR 12.0%
RRR 14.9%
(95% CI 0.6-22.1)
NNT 26
ARR 3.9%
(95% CI 0.3-27.3)
NNT 29
ARR 3.4%
IS, MI, VD
IS, MI, rehospitalization
* 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.
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
8146 patients treated with DES (sirolimus or paclitaxeleluting 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
Daemen J et al. Lancet 2007;369:667–78
Duke Registry – clopidogrel and longterm outcomes after DES implantation
Adjusted rates of death or MI starting at 6 months
Difference = -4.1 ± 3.5
Difference = -0.5 ± 2.7
p=0.02
p=0.70
• Adjusted outcomes
were analyzed at 24
months
Endpoint (%)
• Patients in the DES
with clopidogrel group
had significantly lower
rates of death or MI
than did patients in
the DES without
clopidogrel group
• Among BMS patients,
there were no
differences in death
or MI
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 guidelines
2007 update
Bassand J-P et al. Eur Heart J 2007;28:1598–1660.
NSTE-ACS - recommendations
for oral antiplatelet drugs (2007)
• Aspirin is recommended for all patients presenting
with NSTE-ACS without contraindication at an
initial loading dose of 160 - 325mg (non-enteric) (IA), and at a maintenance dose of 75 to 100mg longterm (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)
Bassand J-P et al. Eur Heart J 2007;28:1598–1660.
28
ESC PCI 2005 guidelines
Silber S et al. Eur Heart J 2005;26:804-47.
PCI - recommendations
for oral antiplatelet drugs (2005)
• 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), drugeluting 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)
Silber S et al. Eur Heart J 2005;26:804-47.
International updates
King SB III et al. Circulation 2008;117:261-95.
International updates –
US PCI guidelines (2007)
• 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)
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.
B.
C.
D.
E.
1 month
6 months
9 months
12 months
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.
B.
C.
D.
E.
1 month
6 months
12 months
24 months
36 months
Many thanks
for further slides on this topic, please
visit the www.metcardio.org website