Giovanni Maria SantoroS. C. Cardiologia

Ospedale San Giovanni di Dio Firenze

Gestione del paziente con stent coronarico. Il mantenimento della doppia antiaggregazione a lungo

termine

Efficacy of Dual Antiplatelet Therapy in Reducing Coronary Events after

Stenting

Early stent thrombosis in patients treated with BMS

Cutlip et al. Circulation 2001;103:1967-71

Acute stent thrombosis < 24 h

Subacute stent thrombosis

24 h - 1 month

Cumulative incidence at 3 yrs 2.9%Predictors of stent thrombosis

ACS HR 2.28 95% CI 1.29-4.03Diabetes HR 2.07 95% CI 1.07-3.83

Stent Thrombosis of DES Data from a large two institutional cohort study

Daemen J et al. Lancet 2007;369:667-668

Histological characterization of DES vs BMS

Endhotelialization in DES vs BMS

Independent predictors of stent thrombosis

Iakovou I, Colombo A, et al. JAMA 2005; 293:2126-30

Long-term dual antiplatelet therapy

Main open issues

Clopidogrel low

responsiveness

Perioperative management

Chronic oral anticoagulation

Interaction with PPIs

Clopidogrel absorption, metabolism and target

Definite/Probable DES thrombosis Definite/Probable DES thrombosis at 6-month FUat 6-month FU

0

2

4

6

8

10 % stentthrombosis

All pts(n=804)

Clop-Resp(n=699, 87%)

Clop-nonResp(n=105, 13%)

2.3 (n=16)

P < .0001

8.6 (n=9)

3.1 (n=25)

804 unselected consecutive pts with CAD (2/3

UA/STEMI) with DES implanted, on ASA and clopidogrel

(600 mg loading dose + 75 mg/day chronically for

almost six months)

Buonamici et al. J Am Coll Cardiol 2007;49:2312

Long-term dual antiplatelet therapy

Main open issues

Clopidogrel low

responsiveness

Perioperative management

Chronic oral anticoagulation

Interaction with PPIs

Risk of discontinuing antiplatelet therapy and increasing the

possibility of perioperative stent

thrombosis

Risk of continuing antiplatelet therapy and

increasing the possibility of surgical

bleeding

The perioperative dilemma

noncardiac surgery increases the risk of stent thrombosis early surgery carries significantly greater risk than delayed surgery the risk increases when antiplatelet therapy is discontinued

Coronary stent thrombosis and noncardiac surgery

ACC/AHA 2007 Guidelines on Perioperative Cardiovascular ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac SurgeryEvaluation and Care for Noncardiac Surgery

DELAY SURGERY

Continue dual antiplatelet therapy

during and after surgery

MINIMIZE THE RISK OF STENT THROMBOSIS

Stop clopidogrel and aspirin and “bridge”

with a short-acting GP IIb-IIIa inhibitor

Continue aspirin, stop clopidogrel and

restart it soon after surgery

Ris

k o

f b

leed

ing

Heparin probably ineffective because stent thrombosis is primarily a platelet-mediated

phenomenon.

Long-term dual antiplatelet therapy

Main open issues

Clopidogrel low

responsiveness

Perioperative management

Chronic oral anticoagulation

Interaction with PPIs

Risk of discontinuing warfarin and increasing the possibility of stroke

or thromboembolic events

Risk of discontinuing clopidodrel and increasing the

possibility of stent thrombosis

The triple dilemma of triple therapy

Risk of continuing warfarin + aspirin + clopidogrel and

increasing the possibility of

bleeding

Triple therapy and major bleeding

@ 30 days 6.0%

@ 6 months13.3%

@ ≥ 12 months13.3%

Rubboli et al. Ann Med 2008;40:428-36

What to do in patients with DES who need warfarin?

DO NOT STOP CLOPIDOGREL PREMATURELY

Add warfarin to clopidogrel and aspirin if < 1 month after BMS or < 1 year after DES implantation.

Limit the time of triple therapy as much as possible, containing aspirin dose to ≤100 mg and targeting INR to 2.0-2.5.

A combination of warfarin and one antiplatelet agent seem to be a better choice for long-term treatment after stent implantation.

Since the most frequent bleeding site is gastro-intestinal, strategies to reduce GI events are recommended.

Long-term dual antiplatelet therapy

Main open issues

Clopidogrel low

responsiveness

Perioperative management

Chronic oral anticoagulation

Interaction with PPIs

Clopidogrel is a prodrug; requires conversion by the liver primarily Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolitevia CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity

Clopidogrel and PPIs – The OCLA studyClopidogrel and PPIs – The OCLA study

-32,6

-43,3-50

-40

-30

-20

-10

0

PR

I V

aria

tio

n (

%)

Omeprazole (n=64)

Placebo (n=60)

PRI: Platelet Reactivity Index – change at day 7 from baseline

Gilard et al. J Am Coll Cardiol 2008;51:256-60.

p<0.0001

clopidogrel

clopidogrel + omeprazole

Risk of All-Cause Mortality and Recurrent ACS

in Patients Taking Clopidogrel and PPIOf 8205 patients with ACS taking clopidogrel after hospital discharge,

63.9% (n=5244) were prescribed PPI at discharge

Clopidogrel + PPI

Clopidogrel / noPPI

Ho et al. JAMA. 2009;301(9):937-944.

• Multicenter, international, randomized, double-blind, placebo-controlled trial

• Comparison of a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), with clopidogrel (75 mg) alone.

• All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg.

• 3627 patients included, median follow-up 133 days (max 366 days)

The COGENT TrialThe COGENT Trial

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite Cardiovascular Events

Adjustment through Cox Proportional Hazards ModelAdjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusAdjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 1.0295% CI = 0.70; 1.51

Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

PlaceboTreated

Survival Curves for PPI Treated vs PlaceboMI Events

Adjustment through Cox Proportional Hazards ModelAdjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusAdjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 0.9695% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk

Treated: 36 events, 1839 at risk

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboRevascularization

Adjustment through Cox Proportional Hazards ModelAdjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusAdjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 0.9595% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk

Treated: 69 events, 1806 at risk

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite GI Events

HR = 0.5595% CI = 0.36; 0.85

p=0.007 Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk

Conclusions

COGENT is the first, randomized assessment of clopidogrel and PPIs on clinical events

The data provide strong reassurance that there is no clinically relevant adverse cardiovascular interaction between clopidogrel and omeprazole

The results support the use of prophylactic PPIs, although the optimal strategy to reduce GI events in patients on antithrombotic therapy is still needed to define.

CV

dea

th,

MI

or

stro

ke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

Major bleeding risk Triple therapy vs Double

therapy

Sourgounis et al. Circulation 2009;119:1682-88

Major bleeding Relative Risk 4.16 (95% CI 2.08-8.33)

- sympathetic activation

- increased inflammatory mediator release

- increased platelet adhesiveness and persistently high platelet counts

- increase release of procoagulant factors

- decreased/impaired fibrinolysis

Noncardiac surgery and risk of stent thrombosis

incomplete endhotelialization of the stent rebound after interruption of antiplatelet therapy

- increased platelet adhesion and aggregation

- increased inflammatory prothrombotic state

increased prothrombotic and inflammatory state associated with surgery