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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