Minimaster Cuore e diabete Prevenzione delle recidive e aderenza alle terapie Cardioprotezione...

Minimaster Cuore e diabetePrevenzione delle recidive e

aderenza alle terapie

Cardioprotezione farmacologica: il punto sul clopidogrel

Massimo Uguccioni

Roma

Il clopidogrel in associazione all’ASA nella pratica clinica

• Pazienti con N-STEMI e/o PCI• Benefici nei pazienti con STEMI• Esiste un’indicazione in prevenzione

primaria?• Pazienti con stent (BMS e DES)• Uso del clopidogrel nel mondo reale• Terapia anti-aggregante e chirurgia non

cardiaca

Clopidogrel Evidence: ACS (Non-STEMI - UA)

Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial

The CURE Trial Investigators. NEJM. 2001;345:494-502

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0,14

3 6 90 12

Rat

e o

f d

eath

, m

yoca

rdia

l in

farc

tio

n,

or

stro

ke

20% RRR P<0.001

Months of Follow Up

Aspirin + Clopidogrel

Aspirin + Placebo

12,562 patients with a NSTEMI-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 3-12 months (average 9)

PCI – CurePCI – Cure

Mehta et al. Lancet 2001;358:527-533Steinhubl S et al. JAMA. 2002; 288:2411-2420

MI,

Str

ok

e o

r D

eath

(%

)M

I, S

tro

ke

or

Dea

th (

%)

Months From RandomizationMonths From Randomization

27%27%RRRRRR

Placebo*Placebo*Clopidogrel*Clopidogrel*

00

55

1010

1515

8.5%8.5%

11.5%11.5%

00 33 66 99 1212

††up to 12 months ‡plus ASA and other standard therapies

PlaceboPlacebo‡‡ ClopidogrelClopidogrel‡‡

1515

1010

55

00

0 100100 200200 300300 400400Days of follow-upDays of follow-up

12.6%12.6%

8.8%8.8%

P P = 0.002= 0.002N = 2658N = 2658

CV

-de

ath

or

MI

(%

)C

V-d

eat

h o

r M

I (

%) 31%31%

RRRRRR

PP=0.02=0.02

N = 2116N = 2116

CREDOCREDO

PCI-CURE and CREDOLong-Term Benefits of Clopidogrel in PCI Patients




cardiaca

*Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization

Time (days)

Pat

ien

ts w

ith

en

dp

oin

t (%

)

0

5

10

15

0 5 10 15 20 25 30

20%*p=0.03

Clopidogrel(11.6%)

Placebo (14.1%)

Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

Clopidogrel Reduced Clinical Events by 20% at 30 Days

0 7 14 21 280

1

2

34

5

67

8

910

Days (up to 28 days)

Clopidogrel(9.3%)

Placebo (10.1%)

Eve

nts

(%

)

RRR=9%p=0.002

RRR = relative risk reduction

Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.

Clopidogrel Reduced the Composite of Death, MI or Stroke by 9%




cardiaca

0

2

4

6

8

CHARISMA Primary Outcome (MI, Stroke, or CV Death)Primary Outcome (MI, Stroke, or CV Death)

Cum

ula

tive E

vent

Rate

(%

)

Months Since Randomization

0 6 12 18 24 30

Placebo + ASA7.3%

First occurrence of fatal or non-fatal MI, fatal or non-fatal stroke, or CV deathAll patients received ASA (aspirin) 75-162 mg/day

Bhatt DL et al. N Engl J Med 2006;354:1706–1717.

RRR: 7.1% [95% CI: -4.5%, 17.5%]P=0.22

Clopidogrel + ASA6.8%

P = 0.22

Van de Werf, F. Eur Heart J Suppl 2007 9:D3-9D

Effect of aspirin plus clopidogrel on the primary endpoint (MI, stroke, CV death) in patients with risk factors or

established disease

Absolute benefit and bleeding hazard of combined treatment with clopidogrel plus aspirin




cardiaca

Start and continue clopidogrel 75 mg/d in combination with aspirin

for post ACS or post PCI with stent placement patients for up to 12 months

for post PCI-stented patients

>1 month for bare metal stent,

>3 months for sirolimus-eluting stent

>6 months for paclitaxel-eluting stent

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Clopidogrel Recommendations




cardiaca

Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

Comparison of treatment of STEMI patients at discharge in ACS-I and ACS-II in 34 centres

European Heart Survey (2000-04)

Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

Comparison of treatment of N-STEMI patients at discharge in ACS-I and ACS-II in 34 centres

European Heart Survey (2000-04)

Variations Among Hospitals430 CRUSADE hospitals

95%86%

91%

50%

86%

65%71%

21%

0%

20%

40%

60%

80%

100%

Aspirin Beta Blockers Heparin GP IIb-IIIa

Leading Centers

Lagging Centers

94%89%

68%

81%

60%

82%

69%

49%

64%

36%

0%

20%

40%

60%

80%

100%

ASA B Blocker ACE* Statin* Clopidogrel

94%89%

68%

81%

60%

82%

69%

49%

64%

36%

0%

20%

40%

60%

80%

100%

ASA B Blocker ACE* Statin* Clopidogrel

AcuteAcute DischargeDischarge

Peterson et al, JAMA 2006;295:1863-1912Peterson et al, JAMA 2006;295:1863-1912

92

61,7

84

60,3

70,3

91,9

58,5

84,1

59,6

68,7

87,9

47,4

82,8

6156,6

40

50

60

70

80

90

100

ASA Clopidogrel B-Blocker ACE-I Statin

Low-Risk Moderate-Risk High-Risk

92

61,7

84

60,3

70,3

91,9

58,5

84,1

59,6

68,7

87,9

47,4

82,8

6156,6

40

50

60

70

80

90

100

ASA Clopidogrel B-Blocker ACE-I Statin

Low-Risk Moderate-Risk High-Risk

Paradoxical Discharge Care Patterns (n = 74,217 patients in CRUSADE)

Late DES Thrombosis

Independent Predictors of Late Thrombosis

Iakovou JAMA 2005; 293: 2126-30

29,0%

8,7%5,5%

3,5% 3,2% 2,6%1,3%

**AntiplateletTherapy

Discontinuation

DiabetesDiabetesPriorPriorBrachyBrachy

RenalRenalFailureFailure

BifurcationBifurcation ULMULM UAUA

*Premature discontinuation

Stent Thrombosis RatesSelected Patient Characteristics

Jeremias P et al Circulation 2004; 293:2126

Spertus, J. A. et al. Circulation 2006;113:2803-2809

Mortality from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month after MI

Premier Registry 19-center study – 500 DES treated

13.6% stop therapy in 30 days

Spertus, J. A. et al. Circulation 2006;113:2803-2809

Cardiac rehospitalization from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month

Premier Registry 19-center study

DES-CDES-C

BMS-CBMS-C

DES+CDES+C

BMS+CBMS+C

00

22

44

66

88

Per

cen

t C

um

ula

tive

Inci

den

ce

Rat

e P

erce

nt

Cu

mu

lati

ve In

cid

ence

R

ate

1212 1818 242466

0.700.70-0.5-0.5BMS+C BMS-CBMS+C BMS-C

0.440.441.21.2DES-C BMS-CDES-C BMS-C

0.010.01-2.9-2.9DES+C BMS-CDES+C BMS-C

0.160.16-2.4-2.4DES+CBMS+CDES+CBMS+C

0.020.02-4.1-4.1DES+C DES-CDES+C DES-C

pp% (95% CI)% (95% CI)7.27.2

5.55.5

6.06.0

3.13.1

MonthsMonths

Eisenstein, E et al. JAMA 2007; 297(2):159-68Eisenstein, E et al. JAMA 2007; 297(2):159-68

n=4666n=4666

Duke Databank 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or

Nonfatal MI

Windecker, S. et al. Circulation 2007;116:1952-1965

Antiplatelet treatment at the time of DES thrombosis in 152 patients

Results: Predictors of inappropriate clopidogrel use

Predictors OR (95% C.I)

Age 0.97 (0.97-0.98)

Female gender 0.79 (0.69-0.91)

Diabetes 1.2 (1.0-1.4)

Medicare insurance 1.5 (1.26-1.81)

0.02

0.04

0.06

0.08

0.10

Cu

mm

ulat

ive

inci

den

ce

0 1 2 3Years

Appropriate clopidogrel adherence

Innappropriate clopidogrel adherence

Results: Incidence of MI by adherence to clopidogrel

HR 1.35(1.08-1.70)p=0.009

• Dual anti-platelet discontinuation

• DM

• ACS / AMI

• Low EF

• Renal Failure

• Bifurcations

• Longer stent length

• Residual dissection

• Small stent diameter

• Stent underexpansion

• Malapposition

Patient Factors Lesion Factors

Who Should Not Get DES in 2007?Who Should Not Get DES in 2007?

Predictors of Stent Thrombosis

UA/NSTEMI Groups at Discharge

UA/NSTEMI Groups at Discharge

Medical RxNo Stent

Medical RxNo Stent

Bare Metal Stent

Bare Metal Stent

Drug-Eluting Stent

Drug-Eluting Stent

ASA 75-162 mg/d indefinitely

Clopidogrel 75 mg/d> 1 mo (Class I, LOE A)

up to 1 yr (Class I, LOE B)

ASA 75-162 mg/d indefinitely

Clopidogrel 75 mg/d> 1 mo (Class I, LOE A)

up to 1 yr (Class I, LOE B)

ASA 162-325 mg/d for 1 mothen 75-162 mg/d

indefinitely

Clopidogrel 75 mg/dfor at least 1 mo and up to

1 yr (Class I, LOE B)

ASA 162-325 mg/d for 1 mothen 75-162 mg/d

indefinitely

Clopidogrel 75 mg/dfor at least 1 mo and up to

1 yr (Class I, LOE B)

ASA 162-325 mg/d for 3-6 mothen 75-162 mg/d indefinitely

Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B)

ASA 162-325 mg/d for 3-6 mothen 75-162 mg/d indefinitely

Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B)

Indication for AnticoagulationIndication for Anticoagulation

Add Warfarin (Class IIb, LOE B)Add Warfarin (Class IIb, LOE B) Continue dual antiplatelet RxContinue dual antiplatelet Rx

YesYes NoNo

Anderson HV et al. ACC/AHA UA/NSTEMI Guideline Revision. JACC 2007; 50:e1–157Anderson HV et al. ACC/AHA UA/NSTEMI Guideline Revision. JACC 2007; 50:e1–157

ACC/AHA 2007: Long-Term Treatment

Ho PM, et al. JAMA 2008;299(5):532-539

Is There Clinical Evidence of Clopidogrel Rebound?

• Study Population:– 127 VHA Hospital ACS Registry: Oct 2003-March 2005– Admitted with ACS between 10/03 to 9/04– Discharged on clopidogrel

• Total duration of clopidogrel treatment : 50th (25th-75th)– Medical (n=1569): 281 days (120-417)– PCI (n=1568): 310 days (182-410)

• All-cause death/MI after stopping clopidogrel– Determined for each 90 day period

Interval after stoppingclopidogrel

0-90days

91-180days

181-270days

271-360days

361-450days

Patients at risk 1277 1147 565 332 220

Events 56 25 7 4 3

PCI Therapy: Event rates after stopping clopidogrel

Interval after stopping clopidogrel

0-90days

91-180days

181-270days

271-360days

361-450days

Patients at risk 1247 1079 524 335 238

Events 118 46 26 5 8

Medical Therapy: Event rates after stopping clopidogrel

Angiolillo, D. J. et al. Circulation 2007;115:708-716

Platelet aggregation (A) and inhibition of platelet aggregation (B) (baseline and 30 days) after stimulus with ADP in doses of 75

mg and 150 mg in diabetic patients




cardiaca

Presentazione del caso clinico

• Uomo di 55 anni ex-fumatore; accusa tosse persistente.

• Rx torace: opacità vicino al bronco lobare superiore destro

• Tre mesi prima SCA trattata con impianto di DES sulla DA prossimale

• Si rende necessaria una biopsia bronchiale

Riddell, J. W. et al. Circulation 2007;116:e378-e382


Flow chart to determine the risk of stent thrombosisin non cardiac surgery

Expert opinion

Chirurgia odontoiatrica

Gestione del caso clinico

• Si decide per la sospensione del clopidogrel cinque giorni prima della biopsia con ripresa con dose da carico il primo giorno postoperatorio

• La terapia con aspirina non viene sospesa


AHA/ACC/SCAI/ACS/ADA Science Advisory

Summary and Recommendations

1. Patients should be specifically instructed before hospital discharge to contact their cardiologist before stopping any anti-platelet therapy

2. Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine

3. For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent thrombosis.

Conclusions

• While in-hospital antiplatelet therapy is improving, still potential for optimization– More complete treatment, particularly high risk

– More appropriate drug dosing in diabetics?

• Greater potential for improving outpatient care– Better patient adherence

– Better understanding of optimal therapy duration

– Protocols for safe drug withdrawal

Minimaster Cuore e diabete Prevenzione delle recidive e aderenza alle terapie Cardioprotezione...

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