Transcript Presentazione di PowerPoint - Associazione Medici Scandicci

Gestione del paziente con stent coronarico.
Il mantenimento della doppia
antiaggregazione a lungo termine
Giovanni Maria Santoro
S. C. Cardiologia
Ospedale San Giovanni di Dio
Firenze
Efficacy of Dual Antiplatelet Therapy in
Reducing Coronary Events after Stenting
Early stent thrombosis in patients treated with BMS
Subacute stent thrombosis
24 h - 1 month
Acute stent thrombosis < 24 h
Cutlip et al. Circulation 2001;103:1967-71
Stent Thrombosis of DES
Data from a large two institutional cohort study
Cumulative incidence at 3 yrs 2.9%
Predictors of stent thrombosis
ACS
HR
Diabetes HR
2.28 95% CI 1.29-4.03
2.07 95% CI 1.07-3.83
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
at 6-month FU
 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)
10
% stent
thrombosis
P < .0001
8.6 (n=9)
8
6
3.1 (n=25)
4
2.3 (n=16)
2
0
Buonamici et al. J Am Coll Cardiol 2007;49:2312
All pts
(n=804)
Clop-nonResp
Clop-Resp
(n=699, 87%) (n=105, 13%)
Long-term dual antiplatelet therapy
Main open issues
 Clopidogrel low responsiveness
 Perioperative management
 Chronic oral anticoagulation
 Interaction with PPIs
The perioperative dilemma
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
Coronary stent thrombosis and noncardiac surgery
 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
DELAY SURGERY
ACC/AHA 2007 Guidelines on Perioperative Cardiovascular
Evaluation and Care for Noncardiac Surgery
MINIMIZE THE RISK OF STENT THROMBOSIS
Continue dual antiplatelet therapy
during and after surgery
Continue aspirin, stop clopidogrel and
restart it soon after surgery
Stop clopidogrel and aspirin and “bridge”
with a short-acting GP IIb-IIIa inhibitor
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
The triple dilemma of triple therapy
Risk of discontinuing
clopidodrel and increasing
the possibility of stent
thrombosis
Risk of continuing
warfarin + aspirin
+ clopidogrel and
increasing the
possibility of bleeding
Risk of discontinuing
warfarin and increasing the
possibility of stroke or
thromboembolic events
Triple therapy and major bleeding
@ 30 days
6.0%
@ 6 months
13.3%
@ ≥ 12 months
13.3%
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 2.02.5.
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 and PPIs – The OCLA study
Clopidogrel is a prodrug; requires conversion by the liver primarily via
CYP3A4 and CYP2C19 to an active metabolite
PPIs are strong inhibitors of CYP2C19 activity
PRI: Platelet Reactivity Index – change at day 7 from baseline
PRI Variation (%)
0
-10
-20
Omeprazole (n=64)
clopidogrel
Placebo (n=60)
clopidogrel + omeprazole
-30
-40
-32,6
-43,3
-50
p<0.0001
Gilard et al. J Am Coll Cardiol 2008;51:256-60.
Risk of All-Cause Mortality and Recurrent ACS
in Patients Taking Clopidogrel and PPI
Of 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.
The COGENT Trial
• Multicenter, international, randomized, double-blind, placebocontrolled 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)
0.96
0.94
Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
HR = 1.02
95% CI = 0.70; 1.51
Placebo
0.92
0.90
Survival Probability
0.98
1.00
Survival Curves for PPI Treated vs Placebo
Composite Cardiovascular Events
Treated
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
0
30
60
90
120
150
180
210
Days
240
270
300
330
360
390
1.00
Survival Curves for PPI Treated vs Placebo
MI Events
0.94
0.96
Placebo
HR = 0.96
95% CI = 0.59; 1.56
Placebo: 37 events, 1851 at risk
Treated: 36 events, 1839 at risk
0.92
0.90
Survival Probability
0.98
Treated
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
0
30
60
90
120
150
180
210
Days
240
270
300
330
360
390
0.98
1.00
Survival Curves for PPI Treated vs Placebo
Revascularization
Treated
0.96
0.94
HR = 0.95
95% CI = 0.59; 1.55
Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
0.92
0.90
Survival Probability
Placebo
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
0
30
60
90
120
150
180
210
Days
240
270
300
330
360
390
0.98
1.00
Survival Curves for PPI Treated vs Placebo
Composite GI Events
0.96
0.94
Placebo
HR = 0.55
95% CI = 0.36; 0.85
0.92
p=0.007
Placebo: 67 events, 1895 at risk
Treated: 38 events, 1878 at risk
0.90
Survival Probability
Treated
0
30
60
90
120
150
180
210
Days
240
270
300
330
360
390
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.
Primary endpoint stratified by use of a PPI
PPI use at randomization (n= 4529)
CV death, MI or stroke
14%
12%
10%
PPI
PPI
No PPI Prasugrel
8%
6%
4%
CLOPIDOGREL
PPI vs no PPI:
Adj HR 0.94, 95% CI 0.80-1.11
PRASUGREL
PPI vs no PPI:
Adj HR 1.00, 95% CI 0.84-1.20
2%
0%
0
100
200
300
Clopidogrel
No PPI
400
Days
O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.
Major bleeding risk
Triple therapy vs Double therapy
Major bleeding Relative Risk 4.16
(95% CI 2.08-8.33)
Sourgounis et al. Circulation 2009;119:1682-88
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
- sympathetic activation
- increased inflammatory mediator release
- increased platelet adhesiveness and persistently
high platelet counts
- increase release of procoagulant factors
- decreased/impaired fibrinolysis