Strategie di Prevenzione del Rischio CCV Globale Bergamo 13 Novembre 2010 Roberta Rossini USC Cardiologia Ospedali Riuniti di Bergamo Aderenza terapeutica: il fattore di rischio occulto
Strategie di Prevenzione del Rischio CCV Globale
Bergamo 13 Novembre 2010
Roberta Rossini
USC Cardiologia Ospedali Riuniti di Bergamo
Aderenza terapeutica:
il fattore di rischio occulto
“I farmaci non funzionano nei pazienti che non li assumono”
C. Everett Koop, MD
Copyright ©2006 American Heart AssociationNewby, L. K. et al. Circulation 2006;113:203-212
Prevalence of use of aspirin, beta-blockers, lipid-lowering agents in patients with coronary artery disease
Impatto dell’interruzione precoce delle “evidence-based medical therapies” sulla prognosi clinica dopo
Infarto Miocardico Acuto: dati del Registro PREMIER
Impatto dellImpatto dell’’ interruzione precoce delle interruzione precoce delle ““ evidenceevidence--based medical based medical therapiestherapies”” sulla prognosi clinica dopo sulla prognosi clinica dopo
Infarto Miocardico Acuto: dati del Registro PREMIERInfarto Miocardico Acuto: dati del Registro PREMIER
Ho PM, et al.Arch Intern Med. 2006;166:1842-1847
HR
Interruzione dell’Aspirina
Interruzione dei Beta-bloccanti
Interruzione delle Statine
Riduzione della Mortalità Aumento della Mortalità
Copyright ©2010 American Heart AssociationBaroletti, S. et al. Circulation 2010;121:1455-1458
Causes of medication nonadherence
Khouzam RN, JACC 2 November 2010
A heart with 67 stents
Stent metallici (BMS)
Duplice antiaggregazione dopo
impianto di stent coronarici
Classe I
For post-PCI patients receiving a BMS, dual antipla telet therapy should be
given for a minimum of 1 month (level of Evidence: A)
ACC/AHA 2007 PCI Guidelines update
PCI Guidelines 2005
Classe IIn patients who have undergone PCI, clopidogrel 75 mg daily should be given for at least 3 months after sirolimus stent implantation, and 6 months after paclitaxel stent implantation, and ideally up to 12 months in patients who are not at high risk of bleeding.
(Level of Evidence: B)
PCI Guidelines UPDATE 2007Classe I
For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding.
(Level of Evidence: B)
Durata della duplice antiaggregazione dopo
impianto di stent medicati
ACC/AHA PCI Guidelines
Ospedali Riuniti di Bergamo
GP, male, 86 yrs old
• Dyslipidemia, COPD. Hb 11 g/dl
• 2002 anterior MI�primary PCI (BMS) on mid LAD
• June 2006 PCI on prox LAD (DES) for stable angina
• Oct 2006 Aspirin and Clopidogrel discontinuation due to melena and
subsequent gastroscopy
• Oct 2006 at 12:00 chest pain
• 16:20 at ER – Anterior AMI – Aspirin 250 mg i.v. –Heparin 5000 UI
GP, male, 86 yrs old
Ospedali Riuniti di Bergamo
• 16:30 cath lab arrival
• SBP 70 mmHg-Killip IV – Clopidogrel 300 mg
• 16:35 Coronary angiography starts
Pathology of DES in Humans
Temporal sequence of reendothelialization in BMS and DES
Pathology of DES in Humans
Temporal sequence of reendothelialization in BMS and DES
Joner et al., JACC 2006 48:193-202Joner et al., JACC 2006 48:193-202
68 DES > 30 days68 DES > 30 days
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 111516 2017Months
%
E
ndo
the
lializ
atio
n
DES
BMS
>400
20
40
60
80
100
1 2 3 4 5 6 7 8 9 111516 2017Months
%
E
ndo
the
lializ
atio
n
DES
BMS
>40
DESDES
BMSBMS
Premature Discontinuation of Antiplatelet Therapy as Predictor of ST
Premature Discontinuation of Antiplatelet Therapy as Predictor of ST
OR=89.8(29.9-270)
HR=19.2(5.6-65.5)
OR=4.8(2.0-11.1)
HR=13.7(4.0-46.7)
Odd
s/H
azar
dR
atio
Iakovou et alJAMA 2005
Park et alAm J CARD 2006
Kuchulakanti et alCirculation 2006
Airoldi et alCirculation 2006
We studied 1358 consecutive pts treated with DES and discharged on dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day)
Clopidogrel was to be maintained for 12 months
Pts were followed-up for 32.4±11.3 months
86,4%
8,8% 4,8%
No discontinuation
Early discontinuation
Late discontinuation Rossini R et al. Am J Card 2011, in press
Discontinuation Causes:
� Surgery 34.5% � Bleeding 21%� Medical decision 17.6%� Dental interventions 7.6%� Economic/burocratic reasons 5.9% � Anticoagulant therapy 5.0%
Patients who discontinued antiplatelet therapy had a higher incidence of death, MACE and stent thrombosis
MACE
%
Discontinuation and Prognosis
Rossini R et al. Am J Card 2011, in press
Death, MACE or stent thrombosis and time of discontinuationDeath, MACE or stent thrombosis and time of discontinuation
%
P=0.10
P=0.02
P=0.008
P for trend = 0.004
P=0.10
P=0.02
P=0.008
P for trend = 0.004P=0.10
P=0.02
P=0.008
P for trend = 0.004
Rossini R et al. Am J Card 2011, in press
Any Discontinuation� history of prior stroke (OR=4.46, p=0.018) � statins at discharge (OR=0.35, p<0.001)� oral anticoagulants at discharge (OR=5.94, p<0.001)� in-hospital major bleeding(OR=7.69, p<0.001)� In-hospital minor bleeding (OR=2.17, p=0.028)
Predictors of Discontinuation
Early Discontinuation� in-hospital major bleeding (OR=9.00, p<0.001)� statins at discharge (OR=0.36, p<0.001)�oral anticoagulants at discharge (OR=8.21, p<0.001)
Late Discontinuation� history of prior stroke (OR=5.21, p<0.001)
Rossini R et al. Am J Card 2011, in press
Mehran RM et al. Eur Heart J 2009 June ; 30: 1457-1466
Influence of Major Bleeding and MI within 30 Days on Risk of Death Over 1 Year
Cox model adjusted for 36 baseline predictors, with MI and majorbleeding (non-CABG) as time-updated covariates
Cox model adjusted for 36 baseline predictors, with MI and majorbleeding (non-CABG) as time-updated covariates
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Myocardial infarction 3.1 (2.4-3.9) <0.001
Major bleeding 3.5 (2.7-4.4) <0.001
Blood transfusion 4.5 (3.4-5.9) <0.001
HR ± 95% CI P-valueHR (95% CI)
% 23,6
47,3
12,712,5
3,13,8
0
10
20
30
40
50
mortality MACE stentthrombosis
Major Bleeding and Long-Term Outcome
Major bleeding
No major bleeding
P<0.001
P<0.001
P=0.002
Rossini R, Musumeci G et al. ESC Congress 2010, Stockholm August 2010
We studied 1437 consecutive pts treated with DES and discharged on dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day)
63,6
11,5
0
10
20
30
40
50
60
70
80
90
100
Major Bleeding and Antiplatelet Discontinuation
Major bleeding
No major bleeding
%
Antiplatelet Discontinuation
Rossini R, Musumeci G et al. ESC Congress 2010, Stockholm August 2010
Major bleeding
� Anemia at admission (OR =8.5 [3.7-19.2], p<0.001)�Oral anticoagulants at discharge (OR=8.4 [1.9-36.2], p=0.004);�Male sex (OR=0.39 [0.16-0.97], p=0.042);�Use of glycoprotein IIb/IIIa inhibitors (OR=2.5 [1.1-5.6], p=0.026)
Minor bleeding
� Oral anticoagulants at discharge (OR=6.2 [2.1-18.1], p=0.001);�Anaemia at admission (OR=2.7 [1.4-5.5], p=0.005);�Prior myocardial infarction (OR=2.0 [1.1-3.9], p=0.032);�Age (OR 1.03 [1.01-1.06], p=0.013)
Independent predictors of cumulativebleeding
Rossini R et al. J Am Coll Card 2010, abstr 2504. Atlanta March 2010
Discharge after acute coronary event
27.3% of patients discontinued statin therapy
during the 12-month follow-up
Median time to discontinuation 35 days (IQR 21–79)
2234 patients; 1385 men; mean age 72 years
IQR = interquartile range
100
90
80
70
0
Pat
ien
ts o
n t
reat
men
t (%
)
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (days)
Discontinuation of statin therapy after ACSDiscontinuation of statin therapy after ACS
Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):68
Statin Discontinuation after MI and long-term MortalityUnited Kingdom General Practice Research Database (n=9939)
Statin Discontinuation after MI and long-term MortalityUnited Kingdom General Practice Research Database (n=9939)
Daskalopoulou S et al. Eur Heart J 2008 29(17): 2083-2091
Reported Side Effects
� Dyspepsia
� Fatigue
� Headache
� Myalgias
� Asymptomatic increase in liver enzymes
� Asymptomatic increase in total CK
“Too many pills”
CK = creatine kinase
Reported causes of discontinuation of statin therapy after an acute coronary event
Reported causes of discontinuation of statin therapy after an acute coronary event
Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):68
Conclusioni
La scarsa aderenza alla terapia rappresenta un fattore di rischio
occulto
E’ spesso legata ad una comunicazione inefficace o alla
mancanza di motivazione adeguata
L'aumentata complessità, e talvolta scarsa maneggevolezza,
della terapia farmacologica poco si concilia con una
ospedalizzazione sempre più breve, in cui il paziente non
raggiunge la piena consapevolezza della sua patologia
How much is too much?
� Clopidogrel is a prodrug. It requires the conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite
� PPIs are strong inhibitors of CYP2C19 activity
�� Clopidogrel is a prodrug. It requires the conversion by the liveClopidogrel is a prodrug. It requires the conversion by the liver r primarily via CYP3A4 and CYP2C19 to an active metaboliteprimarily via CYP3A4 and CYP2C19 to an active metabolite
�� PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity
Clopidogrel and PPIs Clopidogrel and PPIs –– The OCLA studyThe OCLA study
-32.6
-43.3
-50-45-40-35-30-25-20-15-10-50
PR
I Var
iatio
n (%
)
Omeprazole (n=64)
Placebo (n=60)
PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)
Gilard et al. J Am Coll Cardiol 2008;51:256-60
p<0.0001
MYOCARDIAL INFARCTION
31%
with PPIs
RR (95%CI)
Siller-Matula J Thromb Haemost, 2010 september 10
GASTROINTESTINAL BLEEDING
50%with PPIs
RR (95%CI)
Siller-Matula J Thromb Haemost, 2010 september 10
Days
Sur
viva
l Pro
babi
lity
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.90
0.92
0.94
0.96
0.98
1.00
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
The COGENT Trail. Bhatt D. et al. NEJM, october 6, 2010
HR = 0.5595% CI = 0.36; 0.85
p=0.007
Reduction of GI events by PPI
%
Long-term events
P=0.56
P=0.39
P=0.26
Rossini R et al. Eur Heart J 2010;30:741
%
Long-term events
P=0.518
P=0.974
P=1.00
Rossini R et al. Eur Heart J 2010;30:741
%
One year Outcome: Clopidogrel and PPI in 1328 pts
P=0.46 P=0.62 P=0.67
Rossini R et al. Eur Heart J 2010;30:741
Aspirin Sensitivity Reactions
Gollapude R; JAMA. 2004.292;:3017-3023
Aspirin Desensitization Protocol
Time (min) Aspirin dose (mg)
0 1
30 5
60 10
90 20
210 40
330 100
R. Rossini et al. Am J Cardiol 2008;101:786 –789
Aspirin Desensitization Results(N=52)
Aspirin Desensitization Results(N=52)
94,3
0
20
40
60
80
100
Procedural success
%
6,6
93,4
Pre-PCI desesitization
Post-PCI desesitization
%
%
R. Rossini et al. Am J Cardiol 2008;101:786 –789
82,7
0
20
40
60
80
100
Aspirin at FU
Results: Aspirin use and MACE at one yearResults: Aspirin use and MACE at one year
2 4 6 8 10 120
60
70
80
90
100
Freedom from MACE%
Months
92.3%
N = 4 TVR (PCI = 3 and CABG = 1)
%Stop 17,3%
R. Rossini et al. Am J Cardiol 2008;101:786 –789
Conclusioni
La terapia con statine è attualmente l’unica terapia farmacologica capace di rallentare la progressione della placca ateromasica
La terapia con statine ad alto dosaggio nei pazienti con ACS è sicura ed efficace determinando un beneficio precoce e prolungato rispetto alla terapia con statine a dose standard
L’interruzione prematura o la sostituzione terapeutica di statine ad alto dosaggio con agenti della stessa classe, ma con minore azione ipolipemizzante comporta un peggioramento della prognosi clinica, con aumento della morbilità e mortalitàcardiovascolare
L’interruzione prematura della tp antiaggregante si associa a prognosi sfavorevole ed èdeterminata soprattutto da sanguinamenti ed interventi chirurgici
I sanguinamenti, che si verificano sia in fase acuta che a lungo termine, condizionano sfavorevolmente la prognosi
Prima di scegliere la terapia antiaggregante e la strategia di rivascolarizzazione èimportante stratificare il rischio di prematura interruzione della tp antiaggregante, di sanguinamento e di procedura chirurgica a breve-medio termine
%
One year Outcome: Clopidogrel and PPI in 1328 pts
P=0.99
P=0.05
P=0.05
Rossini R et al. Eur Heart J 2010;30:741
Mehran RM et al. Eur Heart J 2009 June ; 30: 1457-1466
Influence of Major Bleeding and MI within 30 Days on Risk of Death Over 1 Year
Cox model adjusted for 36 baseline predictors, with MI and majorbleeding (non-CABG) as time-updated covariates
Cox model adjusted for 36 baseline predictors, with MI and majorbleeding (non-CABG) as time-updated covariates
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Myocardial infarction 3.1 (2.4-3.9) <0.001
Major bleeding 3.5 (2.7-4.4) <0.001
Blood transfusion 4.5 (3.4-5.9) <0.001
HR ± 95% CI P-valueHR (95% CI)
Death
Log Rank P=0,00013
Nodiscontinuation vs early discontinuation: p < 0.001Nodiscontinuation vs late discontinuation: p = 0.223Early discontinuation vs late discontinuation: p = 0.011Nodiscontinuation vs early+late discontinuation: p = 0.018
No discontinuation
Early Discontinuation
Late discontinuation
Stent Thrombosis
No discontinuation
Early Discontinuation
Late discontinuation Nodiscontinuation vs early discontinuation: p = 0.015Nodiscontinuation vs late discontinuation: p = 0.175Early discontinuation vs late discontinuation: p = 0.653Nodiscontinuation vs early+late discontinuation: p = 0.009
MACE
Nodiscontinuation vs early discontinuation: p < 0.001Nodiscontinuation vs late discontinuation: p = 0.117Early discontinuation vs late discontinuation: p = 0.313Nodiscontinuation vs early+late discontinuation: p < 0.001
No discontinuation
Early Discontinuation
Late discontinuation
25
44,9
10,913
0102030405060708090
100
MACE Antiplateletdiscontinuation
Minor Bleeding and Long-Term Outcome
%
Minor bleeding
No bleeding
P<0.001P=0.001
Rossini R et al. Eur Heart J 2009;30:328
Table 2. Cumulative, 30-day and 12-month rates of any bleeding .
Bleeding at follow upBleeding at 30 days Bleeding at 12 months
No(N=1,286)
Yes(N=151)
P
No
(N=1,371)
Yes(N=166)
P
No
(N=1,314)
Yes(N=123)
Cumulative MACE 12.4 31.1 < 0.001
13.6 30.3 < 0.001
12.7 31.7
Any death 4.6 11.3 0.001 5.0 10.6 0.08 4.7 11.4
MI 4.2 8.6 0.015 4.6 6.1 0.545 4.3 8.1
UA leading to hospitalization 3.8 11.3 < 0.001
4.3 10.6 0.028 3.9 12.3
Non fatal stroke 0.5 1.3 0.240 0.5 3.0 0.061 0.5 1.6
Cumulative cardiac death 1.0 5.3 0.001 1.3 4.5 0.068 1.1 5.7
Any stent thrombosis 3.2 6.6 0.031 3.4 7.6 0.08 3.1 8.1
Log rank = 0.003
A) MACE free survival
No major bleeding at 30 daysMajor bleeding at 30 days
Log rank = 0.051
A) Any ST free survival
No major bleeding at 30 daysMajor bleeding at 30 days
Log rank < 0.001
A) MACE free survival
No major bleeding at 12 monthsMajor bleeding at 12 months
Log rank < 0.001
A) Any ST free survival
No major bleeding at 12 monthsMajor bleeding at 12 months
CV
de
ath
, M
I or
str
oke
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.
Efficacy of Antiplatelet Therapy in Reducing Coronary Events after Stenting
Efficacy of Antiplatelet Therapy in Reducing Coronary Events after Stenting
0,81,6
0,5
5,6 5,7
3,9
6,2
3,6
11
8,3
2,7
0
3
6
9
12
Hall (1996) ISAR (1997) STARS (1998) MATTIS(1998)
FANTASTIC(1998)
ASA+Ticlopidine ASA only ASA + Warfarine
N=226 N=517 N=1653 N=350 N=485
P=0.1
P=0.01
P<0.001
P=0.07P=0.37
Cum
ulat
ive
Eve
nt R
ate
%
Pathology of DES in Humans
Temporal sequence of reendothelialization in BMS and DES
Pathology of DES in Humans
Temporal sequence of reendothelialization in BMS and DES
Joner et al., JACC 2006 48:193-202Joner et al., JACC 2006 48:193-202
68 DES > 30 days68 DES > 30 days
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 111516 2017Months
%
E
ndo
the
lializ
atio
n
DES
BMS
>400
20
40
60
80
100
1 2 3 4 5 6 7 8 9 111516 2017Months
%
E
ndo
the
lializ
atio
n
DES
BMS
>40
DESDES
BMSBMS
Possible Mechanisms Linking Post-Percutaneous Coronary
Intervention Bleeding With Increased Mortality
Doyle B Am Coll Cardiol 2009;53:2019–27
Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI
Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9):937-944
0.70
0.60
0.50
0.40
0.30
0.20
0.10
00 90 180 270 360 450 540 630 720 810 900 990 1080
Days Since Discharge
Pro
po
rtio
n o
f D
eath
s o
r R
ecu
rre
nt A
CS
Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI
Log rank = 0.019
30-day Bleeding and Long-Term Mortality
No major bleeding at 30 daysMajor bleeding at 30 days
Rossini R et al. J Am Coll Card 2010, abstr 2504. Atlanta March 2010
Log rank < 0.001
No major bleeding at 12 monthsMajor bleeding at 12 months
12-month Bleeding and Mortality
Rossini R et al. J Am Coll Card 2010, abstr 2504. Atlanta March 2010
ConclusionConclusionS
urvi
valf
ree
from
Ste
ntT
hrom
bosi
s(%
)
100100
9090
8080
7070
6060
5050
40404848
3636
2424
1212
00
Log rank testOverall: p=0.031No discontinuation vs early discontinuation: p=0.015No discontinuation vs late discontinuation: p=0.175Early discontinuation vs late discontinuation: p=0.653No discontinuation vs early+late discontinuation: p=0.009
Months
Late discontinuation
Early discontinuation
No discontinuation
Overall death and discontinuationOverall death and discontinuation
100100
9090
8080
7070
6060
5050
4040
48483636
24241212
Sur
viva
l(%
)
Months
Log rank testOverall: p=0.001No discontinuation vs early discontinuation: p=0.001No discontinuation vs late discontinuation: p=0.223Early discontinuation vs late discontinuation: p=0.011No discontinuation vs early+late discontinuation: p=0.018
Late discontinuation
Early discontinuation
No discontinuation
Rossini R et al. Am J Card 2011, in press
We studied 1358 consecutive pts treated with DES and discharged on dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day)
Clopidogrel was to be maintained for 12 months
Pts were followed-up for 32.4±11.3 months
86,4%
8,8% 4,8%
No discontinuation
Early discontinuation
Late discontinuation
Discontinuation Causes:
� Surgery 34.5% � Bleeding 21%� Medical decision 17.6%� Dental interventions 7.6%� Economic/burocratic reasons 5.9% � Anticoagulant therapy 5.0%
Premature Discontinuation of Antiplatelet Therapy after Drug Eluting Stent Implantation
Rossini R et al. Am J Card 2011, in press
ConclusionConclusion
100100
9090
8080
7070
6060
5050
4040
4848363624241212
Sur
viva
lfre
efr
om
MA
CE
(%
)
Log rank testOverall: p=0.001No discontinuation vs early discontinuation: p=0.001No discontinuation vs late discontinuation: p=0.223Early discontinuation vs late discontinuation: p=0.011No discontinuation vs early+late discontinuation: p=0.018
Late discontinuation
Early discontinuation
No discontinuation
Association between thienopyridine and/or aspirin discontinuation and MACE stratified by time intervals
Discontinuation of Thienopyridine after DESDiscontinuation of Thienopyridine after DES
Mor
talit
y
%
Discontinued
Continued
1 2 3 4 5 6 7 8 9 10 11 120
5
10
15
p<0.001
Months
7.5 %
0.7 %
Spertus et al, Circulation 2006;113:2803-2809
PREMIER Registry: 500 DES treated MI pts
Possible Mechanisms Linking Post-Percutaneous Coronary
Intervention Bleeding With Increased Mortality
Doyle B Am Coll Cardiol 2009;53:2019–27
Bleeding and dual antiplatelet therapy
1,23,4
0123456789
10
major bleeding minor bleeding
30-day Bleeding
%
12-month Bleeding
3
6,9
0123456789
10
major bleeding minor bleeding
%
We studied 1437 consecutive pts treated with DES and discharged on dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day)
Rossini R, Musumeci G et al. ESC Congress 2010, Stockholm August 2010
25
44,9
10,913
0102030405060708090
100
MACE Antiplateletdiscontinuation
Minor Bleeding and Long-Term Outcome
%
Minor bleeding
No bleeding
P<0.001P=0.001
Rossini R, Musumeci G et al. ESC Congress 2010, Stockholm August 2010
Long-term triple therapy with aspirin, clopidogrel, and warfarin18-month TIMI Major and Minor Bleeding
Long-term triple therapy with aspirin, clopidogrel, and warfarin18-month TIMI Major and Minor Bleeding
%
Mean INR at the time of bleeding was 3.1±0.7
2,9
7,8
22,9
0
5
10
15
Major bleeding Minor bleeding
triple therapy (N=102) dual therapy (N=102)
P=0.6
P=0.1
R. Rossini et al. Am J Cardiol 2008 in press
All bleeding cumulative distribution
100
90
80
70
60
500 200 300 450 600
%
Double therapy
Triple therapy
P=0.13
95.1 %
89.2 %
Days
Ble
edin
g ev
ent f
ree
surv
ival
R. Rossini et al. Am J Cardiol 2008 in press
Long-term triple therapy with aspirin, clopidogrel, and warfarin
100
90
80
70
60
500 200 300 450 600
%
Double therapy
Triple therapy with INR < 2.6
All bleeding cumulative distribution by INR
95.1 %
95.1 %
Days
Ble
edin
g ev
ent f
ree
surv
ival
Triple therapy with INR ≥ 2.6
66.7 %
†
‡
† P<0.0001 vs Double therapy
‡ P<0.0001 vs Triple with INR <2.6R. Rossini et al. Am J Cardiol 2008 in press
Long-term triple therapy with aspirin, clopidogrel, and warfarin
5,84,9
0
5
10
15
20triple therapy dual therapy
%
P=0.7
R. Rossini et al. Am J Cardiol 2008 in press
Long-term triple therapy with aspirin, clopidogrel, and warfarin18-month MACE
Long-term triple therapy with aspirin, clopidogrel, and warfarin18-month MACE
Aspirin Hypersensitivity Related Symptoms(N=52)
Aspirin Hypersensitivity Related Symptoms(N=52)
3929
302
Urticaria Angioedema Asthma Anaphylactic shock
%
%
%
%
R. Rossini et al. Am J Cardiol 2008;101:786 –789
Days
Sur
viva
l Pro
babi
lity
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.90
0.92
0.94
0.96
0.98
1.00
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
COGENT Trial ResultsTCT ‘09
HR = 0.5595% CI = 0.36; 0.85
p=0.007
Reduction of GI events by PPI
%
53,1
1,2
7,8
2,1 2,14,2
0,8 1,7
8,1
3,1 3,1
0
5
10
15
20
25
MACE Death Stent Thrombosis
No PPI (n=170) Lansoprazolo (n=855)
Omeprazolo (n=125) Pantoprazolo (n=178)
One year Outcome: Clopidogrel and PPI in 1328 pts
P=0.46
P=0.62P=0.67
Rossini R et al. Eur Heart J 2009;30:741
Clopidogrel is a prodrug. It requires the conversio n by the liveClopidogrel is a prodrug. It requires the conversio n by the live r primarily via r primarily via CYP3A4 and CYP2C19 to an active metaboliteCYP3A4 and CYP2C19 to an active metabolite
PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity
Clopidogrel and PPIs Clopidogrel and PPIs –– The OCLA studyThe OCLA study
PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)
Gilard et al. J Am Coll Cardiol 2008;51:256-60.
p<0.0001
Studio CURE: Primary Endpoint MI / Stroke / CV Death
Months of Follow-Up
Yusuf S et al. N Engl J Med. 2001;345:494-502.
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cum
ulat
ive
Haz
ard
Rat
e
Clopidogrel + ASA*
3 6 9
Placebo + ASA*
P=0.00009N=12,56220% RRR
0 12*Other standard therapies were used as appropriate.
Duplice antiaggregazione nelle sindromi coronariche acute
NSTEACS
ACCP Guidelines 2008
Aderenza alla terapia
"il coinvolgimento attivo, volontario e collaborativo del paziente,
finalizzato a produrre un risultato terapeutico"
tra i pazienti dimessi dopo un infarto miocardico acuto in terapia
con aspirina, statine e beta-bloccanti, circa il 34% dei pazienti sospende almeno 1 dei 3 farmaci
ed il 12% li sospende tutti e 3 entro il primo mese dalla
dimissione
terapia tra 6 e 12 mesi dopo la diagnosi angiografica di
cardiopatia ischemica Il 71% dei pazienti prosegue la terapia con
aspirina, mentre meno della metàmantiene la terapia con beta-
bloccanti (46%), ipolipemizzanti(44%), e solo il 21% continua la
terapia con tutti e 3 i farmaci.
Newby LK, et al. Circulation. 2006;113:203-212
Newby LK, et al. Circulation. 2006;113:203-212
Switching from intensive to moderate statin therapy after an acute coronary event
Switching from intensive to moderate statin therapy Switching from intensive to moderate statin therapy
after an acute coronary eventafter an acute coronary event
1,321 patients discharged on atorvastatin 80mg/day*
557 (42%) switched to moderate statin therapy
Median time to switching 28 days (IQR 16–67 days)
102 (18%) switched to a lower dose of atorvastatin
Mean dose 24mg/day
327 (59%) switched to simvastatin
Mean dose 27mg/day
57 (16%) switched to pravastatin
Mean dose 40mg/day
41 (7%) switched to fluvastatin
Mean dose 80mg/day
486 (37%) continued atorvastatin
80mg/day
278 (21%) discontinued therapy
Median time to discontinuation 37 days (IQR 19–81 days)
*1321 consecutive patients (886 men, mean age 71.1 ± 8.7 years) discharged on atorvastatin 80mg/day after an ACS in a 6.5-year period
Colivicchi F, et al. Int J Cardiol (2010), doi:10.1016/j.ijcard.2010.07.006
SICI-GISE Consensus DocumentSICI-GISE Consensus Document
�The Italian Society of InterventionalCardiology (GISE) recommends a 12-month dual antiplatelet therapy after DES placement
Journal Cardiovascular Medicine 2007; 10:782-791Journal Cardiovascular Medicine 2007; 10:782-791
Research Only
Not Commercially Available
Research Only
Not Commercially Available
Late Stent Thrombosis
Colivicchi F, et al. Int J Cardiol (2010), doi:10.1016/j.ijcard.2010.07.006
Association between switching and MACEsAssociation between switching and MACEs
Riddell, J. W. et al. Circulation 2007;116:e378-e382
Coronary Stent Thrombosis and Non-cardiac Surgery
Nuovo Protocollo di studioStenting coronarico e chirurgia:
Rischio di trombosi dello stent e rischio emorragico
Rilevare il numero di pazienti con pregresse procedure interventistiche coronariche + stenting sottoposti a interventochirurgico (cardiochirurgia, chirurgia generale, ortopedica, traumatologica, urologica, ginecologica, neurochirurgica, oculistica, dermatologica, odontoiatrica, otorino-laringoiatrica) presso gli OO.RR.Bg nell’arco di 6 anni (2003-2009)
Determinare il rischio di trombosi dello stent e di eventi emorragici nella fase peri- e post-operatoria (30 giorni) in rapporto al tipo di stent e di terapia antiaggregante in corso, ed al tempo intercorso tra impianto di stent e chirurgia
Association between thienopyridine and/or aspirin discontinuation and MACE stratified by time intervals
Association between thienopyridine and/or aspirin discontinuation and MACE stratified by time intervals
Discuntinuation of Both
Discuntinuation of Thienopyridines Only
Discuntinuation of Aspirin Only
No Discontinuation
P=1.0
P=0.88
P = 0.20
P=0.26
P=0.001
P = 0.24P=0.08
P=0.002
P=0.001
P=1.00
P=0.11
P = 0.07
%
Log rank p = 0.019
30-day Bleeding and Long-Term Mortality
No major bleeding at 30 daysMajor bleeding at 30 days
No major bleeding at 12 monthsMajor bleeding at 12 months
Log rank p < 0.001
12-month Bleeding and Long-Term Mortality
Time of major bleeding and long-term outcome
Rossini R, Musumeci G et al. ESC Congress 2010, Stockholm August 2010