La terapia antiaggregante ed anticoagulante nel paziente portatore

Corso di Aggiornamento
nella diagnostica e terapia
CARDIOVASCOLARE
La terapia antiaggregante
ed anticoagulante nel paziente
portatore di stent coronarico
Antonino Stipo
U.O.C. Emodinamica e Cardiologia Interventistica
Ospedale “S. Maria Goretti” Latina
6 novembre 2010
Hotel Enea - Aprilia
background
Il 16 settembre 1977 A. Gruentzig esegue la prima
angioplastica coronarica con pallone
POBA (plain old balloon angioplasty) è gravata da
chiusura acuta del vaso richiedente bypass
aortocoronarico, dissezione coronarica, recoil (ritorno
elastico della parete del vaso), restenosi
background
Dal 1985 U. Sigwart inizia la la sua esperienza
sull' impianto di stent (autoespansibile) in
coronaria.
NEJM 1987;316:701
Nel 1991 P.W. Serruys pubblica i risultati di
un lavoro multicentrico sull'impianto di stent:
18% occlusione trombotica dello stent
8% di mortalità annua
18% di restenosi a 6 mesi
NEJM 1991;324:13
I trials randomizzati controllati
di trattamento farmacologico
dopo impianto di stent coronarici
NEJM
1998
Circulation
1997
Circulation
1998
Circulation
1998
(le definizioni di eventi cardiaci non sono identiche negli studi)
Urban P. et al Circulation 1998;98:2126-2132
Dopo impianto di stent convenzionale
ASA + Tienopiridina riduce gli eventi cardiaci
rispetto ad ASA da solo o con TAO
MACE%
MACE%
MACE%
Study
# Pts
Studied
# Pts
Treated
ASA
Thienopyridine
ASA
Warfarin
ASA
Alone
P
ISAR
517
626
1.6
6.2
…
0.01
FANTASTIC
473
485
5.7†
8.6†
…
0.37
STARS
1653
1965
0.5
2.7
3.6
0.0001
MATTIS
350
350
5.6
11.0
…
0.07
Hall et al
226
358
0.8
…
3.9
0.1
MACE indicates major adverse cardiovascular events; Pts, patients; ASA, aspirin; ISAR, Intracoronary Stenting
and Antithrombotic Regimen trial; FANTASTIC, Full ANTicoagulation versus Aspirin TIClopidine after stent
implantation; STARS, STent Anticoagulation Regimen Study; and MATTIS, Multicenter Aspirin and Ticlopidine
Trial after Intracoronary Stenting.
*Cardiac death, acute MI, or repeat TVR at 30 days (except for the FANTASTIC study).
†Death, MI, or stent occlusion at 6 weeks.
Adapted from ten Berg et al.
Grines CL, et al. Circulation. 2007
5
TAO+ ASA e stent coronarico
Meta-analysis of ISAR, STARS, FANTASTIC e MATTIS (total pts. 2436)
p<0.05
p=NS
p<0.05
Rubboli A et al. Cardiology 2005;104:101-6
p<0.05
p=NS
Efficacia duplice terapia antipiastrinica
Odds Ratio
for death, myocardial infarction
and target vessel revascularization
Anticoagulation plus Aspirin
ISAR
STARS
MATTIS
FANTASTIC
pooled
0 0.5 1.0 1.5 2.0 2.5 3.0
Ticlopidine plus Aspirin Control therapy
better better
Meccanismo della trombosi di stent
• La fisiopatologia della trombosi di stent non è del tutto
nota.
• Sembra essere dovuta soprattutto all'attivazione
piastrinica con l'esternalizzazione del recettori IIb/IIIa per
il legame con il fibrinogeno e l'aggregazione con altre
piastrine.
• Comunque, la trombosi di stent non sembra essere solo
un processo piastrino-dipendente.
• Il danno vascolare generato dall'impianto dello stent
provoca l'esposizione del fattore tissutale con conseguente
attivazione della via estrinseca della coagulazione con
generazione di trombina
L’attivazione piastrinica è uno step chiave
nella trombosi di stent
Piastrine a riposo: superficie
liscia, forma discoidale
Piastrine attivate: forma sferica
con pseudopodi
Adapted from www.akh-wien.ac.at/biomed-research/htx/anatomy.htm. Accessed 31 October,
2002 (Permission obtained from the Center of Biomedical Research, University of Vienna)
Aspirina (acido acetilsalicilico)
L'insorgenza d'azione è rapida, con effetto dopo
un'ora dopo somministrazione orale.
La dose appropriata non è ancora stabilita, varia da
soggetto e soggetto, sembra che si attenui con il
tempo.
Dibattuta la percentuale dell'incidenza di resistenza.
La dose di carico di 500 mg può ridurre i casi di
bassa risposta.
•Barnathan, Circulation 1987; Schwartz, N Engl J Med 1988
•Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet
therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy
in various categories of patients [erratum appears in BMJ 1994;308:1540]. BMJ 1994;308:81-106.
•ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised
trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected
acute myocardial infarction. Lancet 1988;2:349-60.
Aspirina (acido acetilsalicilico)
L'aspirina è un inibitore dose-dipendente
irreversibile della ciclo-ossigenasi (COX) con
parziale inibizione dell'attivazione piastrinica.
Alla dose di 100 mg sopprime quasi
completamente la sintesi del tromboxano A2 nei
soggetti sani e nel paziente con aterosclerosi.
•Barnathan, Circulation 1987; Schwartz, N Engl J Med 1988
•Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet
therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy
in various categories of patients [erratum appears in BMJ 1994;308:1540]. BMJ 1994;308:81-106.
•ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised
trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected
acute myocardial infarction. Lancet 1988;2:349-60.
Tienopiridine
Ticlopidina e Clopidogrel
Blocco dell'attivazione piastrinica indotto
dalla via dell'adenosina-difosfato (ADP) e
l'amplificazione ADP mediata di altri
agonisti
Il massimo della inibizione piastrinica si
ottiene dopo 3-5 giorni, per tale motivo la
dose di carico consente una più rapida
insorgenza d'azione.
Il recupero della funzione piastrinica è lento
dopo l'interruzione.
Tienopiridine
Ticlopidina e Clopidogrel
•
Le due molecole hanno, in combinazione con
l'aspirina, una sovrapponibile efficacia sul piano
clinico ma l'associazione fra aspirina e
clopidogrel un miglior profilo di tollerabilità.
•
Sebbene siano stati segnalati anche con il
clopidogrel casi di porpora trombotica
trombocitopenica, neutropenia ed anemia
aplastica questi eventi avversi sono meno
frequenti che con l'uso della ticlopidina.
Tienopiridine
Ticlopidina e Clopidogrel
•
Il clopidogrel ha ampiamente sostituito la
ticlopidina per il profilo di sicurezza nella
prevenzione della trombosi di stent
•
Attualmente viene somministrato con dose
di carico prima della procedura in elezione
Rischio di sanguinamento per bypass aortocoronarico
con clopidogrel
Early Major/Life Threatening Bleeding
10 (%)
P=0.06
9.6
P=0.52
7.5
5
6.3
5.3
4.4
2.5
0
< 4 Days
> 4 Days
After Discontinuation of Study Drug
Fox KA et al., Circulation 2004
Placebo
Clopidogrel
Activated
Platelet
Clopidogrel
Ticlopidine
Aspirin
ADP
TX A
2
To neighboring
platelet
COX
Platelet
agonists
ADP
ATP
calcium
magnesium
Gp IIb/IIIa
fibrinogen
receptor
IV Gp IIb/IIIa
Inhibitors
Activation

Degranulation
TXA, thromboxane; PDGF, platelet-derived growth factor.

Thrombin
Serotonin
Epinephrine
Collagen
Farmaci Antipiastrinici
▪
Inibitori del Tromboxano A2: acido acetisalicilico
▪ Inibitori della fosfodiesterasi: dipiridamolo
▪ Inibitori GP IIb/IIIa: Abciximab, Eptifibatide, Tirofiban
▪ Antagonisti
▪ Antagonisti
del recettore ADP: clopidogrel ticlopidina,
presugrel, ticagrelor,
elinogrel cangrelor
del recettore PAR-1: Atopaxar, E 5555
Un carico di clopidogrel >600 mg non è associato
ad una soppressione significativamente addizionale
della funzione piastrinica per un limitato assorbimento:
ISAR-CHOICE Study
Von Beckerath N – Circulation 2005
600-mg clopidogrel before PCI reduces
periprocedural MI in patients undergoing PCI
Clopidogrel 600mg
Clopidogrel 300 mg
20
%
15
10
5
0
Death, MI or
TVR at 30dayp=0.041
Peri-procedural
CKMB >2xUL
p=0.014
Patti G et al, Circulation. 2005; 111: 2099-2106
“I risultati dell' ARMYDA-2 trial
supportano l'uso routinario di 600 mg
come dose di carico per PCI programmata
European Society of Cardiology
Guidelines for Percutaneous Coronary Intervention – Eur Heart J 2005; 26:804
Durata
duplice terapia antipiastrinica
• Durante il processo di endotelizzazione dello
stent le maglie di metallo sono trombogene
pertanto una adeguata terapia antipiastrinica
deve essere mantenuta.
• Per gli stent convenzionali (BMS) la durata
nota è di circa 4 settimane
• Per gli stent medicati (DES) le informazioni
non sono così chiare
21
Durata somministrazione di Clopidogrel
in diversi Studi
Ravel:
Sirius:
E-Sirius:
C-Sirius
8 weeks
3months
2months
2months
Taxus I:
Taxus II:
Taxus IV:
6months
6months
6months
Mortalità a 6-12 mesi di stent medicato
Babapulle MN et al., Lancet 2004
Incidenza di infarto miocardico a 6-12 mesi dopo DES
Babapulle MN et al., Lancet 2004
Incidenza trombosi di stent a 6-12 mesi dopo DES
Ravel
Sirius
C-Sirius
E-Sirius
0
0
0.4
2.0
2.0
1.1
0
0.6
0.6
pooled
Taxus-I
DES
0.8
0
0
Taxus-II 0
Taxus-IV
pooled
1.1
0.6
0.5
0.8
0.7
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Rate of Stent Thrombosis (%)
Babapulle MN et al., Lancet 2004
BMS
Trombosi di stent
TAXUS IV
0.3
(n=625)
0.3
1.1%
(n=7)
0.5
p 0.77
Control
0.6
(n=613)
0
30 days
0.2
0,5
30 days to 1 year
0.8%
(n=5)
1
1,5
1 year to 2 years
Reports di Trombosi Tardiva dopo DES
Mc Fadden EP et al., Lancet 2004
Paclitaxel-eluting stent:
Paclitaxel-eluting stent:
Sirolimius eluting stent
Sirolimus-eluting stent:
Day 343
Day 442
Day 335
Day 375
dopo sospensione di
aspirina e clopidogrel
Virmani R et al., Circulation 2004
Sirolimus-eluting stent: Day 550
con trombo occlusivo
reazione da ipersensibilità
Hypersensitivity Reaction after Sirolimus-Eluting
Stent
Late Occlusive Thrombus
Inflammation
within media
Giant cells around
polymer remnant
Virmani R et al., Circulation 2004
ACC/AHA/SCAI recommendations for the
prevention of stent thrombosis after coronary
stent implantation state
At the minimum, patients should be treated with 75
mg clopidogrel and ASA 325mg for 1 month after
BMS implantation,
3 months after sirolimus DES implantation,
6 months after paclitaxel DES implantation, and
ideally,
up to 12 months if they are not at a high-risk for
bleeding.
29
Grines CL, et al. Circulation. 2007 Jan:1-6.
Trombosi di Stent within 6-12 Months after DES
Rate of Stent Thrombosis [%]
4
3.5
3
2
1
0.7
0.6
0.8
0.5
3x SIRIUS TAXUS IVTAXUS VI ARTS II Cypher(n=1510) (n=1314) (n=219) (n=606) Bifurcation
(n=86)
Trombosi di stent
• The incidence of death or MI associated with
angiographically documented stent thrombosis
was 64.4% in a pooled analysis of 6 trials and
registries from the 1990s.
• Mortality rates due to presumed or
documented stent thrombosis range from 20%
to 45%.
31
Grines CL, et al. Circulation. 2007 Jan:1-6.
Trombosi di stent
• Stent thrombosis most commonly occurs in
the first month after stent implantation and
referred to as “subacute stent thrombosis”
• Many cases of “late-stent thrombosis”,
occurring months or years after stent
implantation, have been reported – especially
in patients treated with DES
Grines CL, et al. Circulation. 2007 Jan:1-6.
32
E-Cypher Registry
Predictors at 12 Months of Stent Thrombosis by
Multiple Variable Regression Analysis
Variable
OR (95% CI)
p
2.76 (1.71, 4.29)
<0.0001
presentation
1.75 (1.13, 2.67)
0.0105
1.25 (1.05, 1.50)
0.0122
Postprocedure TIMI flow <3
4.42 (1.80, 9.26)
0.0003
Moderate or heavy calcifications
1.93 (1.29, 2.86)
0.0012
Totally occluded target lesion
1.92 (1.14, 3.11)
0.0107
No. of lesions treated
1.31(1.01, 1.67)
0.0317
>1 vessel disease
1.62 (1.04, 2.60)
0.0383
Clinical
Insulin-dependent diabetes
Acute coronary syndrome at
Age (10-year increment)
Angiographic/procedural
Urban P, et al Circulation. 2006;113:1434-1441
prevenzione trombosi dello stent
prevenzione trombosi dello stent
Stent Thrombosis in High Risk groups
Iakovou I et al. JAMA. 2005;293: 21262130.
“At present, we consider the prolonged (at least 6
months) administration of clopidogrel (in addition to
ASA) as mandatory to avoid late stent thrombosis.
Therefore, in patients undergoing or soon will be
undergoing urgent major extracardiac surgery, DES
should not be implanted. In these patients, bare
stents are probably the safer choice. Physicians and
patients must be made aware that clopidogrel should
not be discontinued too early, even for minor
procedures like dental care.”
European Heart Journal (2005) 26, 804–847
“…. complete healing of the DES may theoretically take
up to 2 years. Registries are important to see whether
the results of the controlled studies can be applied to
everyday practice. The premature discontinuation of
thienopyridines was strongly associated with the
development of stent thrombosis. (Recommendation
for 6–12 months clopidogrel administration after DES: I
C).
In patients in whom prolonged administration of
clopidogrel is known to be unlikely (i.e. major
extracardiac surgery planned soon), DES should be
used with caution. In these patients, bare stents are
probably the safer choice.”
European Heart Journal (2005) 26, 804–847
Genetica della risposta al
clopidogrel
CYP2C19 allele 2 bassi
metabolizzatori, perdita di funzione,
rischio negli omozigoti di trombosi di
stent
CYP2C19 allele 17 guadagno di
funzione, forti metabolizzatori, rischio
di emorragia
Per entrambe le varianti c'e' un ampio
range di risposta,
il comportamento del fenotipo non è
sempre coerente con il genotipo
Hulot et al Blood 2006
Mega et al Circulation suppl 2008
Sibbing et al. Circulation 2010
Wallentin et al Lancet 2010
Misurazione della funzione piastrinica
•VerifyNow P2Y12
•Light transmittance aggregometry 5-20 μm/l ADP
PAP 4 - Chronolog – APACT4
•VASP P2Y12
•Plateworks
•IMPACT R
•IMPACT R ADP
•PFA 100 COL/ADP
•INNOVANCE PFA
Misurazione della funzione
piastrinica
Per identificare i pazienti cui
somministrare farmaci più potenti?
CYPHER®
Photos on file at Abbott Vascular.
TAXUS®
ENDEAVOR
XIENCE V
F-up
30 days
6 months
12 months
Clopidogrel
= 2 months
Pts
97.71% (97.71 - 99.14)
97.71% (97.71 - 99.14)
96.94% (96.94 - 98.73)
Clopidogrel
> 2 months
171
147
95
Pts
99.69% (99.69 - 99.96)
324
97.47% (97.47 - 98.73)
251
97.02% (97.02 - 98.45)
146
Stent Thrombosis
Acute
0.2%
Sub-acute
0%
Late
0%
MATRIX Registry
(12-month interim analysis)
Piscione F et al. GISE 2008/TCT 2008/JIM 2009
+
Rapporto rischio/beneficio?
emorragia
trombembolia arteriosa o venosa
trombosi di stent
trombosi di protesi valvolare
fibrillazione atriale parossistica,
persistente o
permanente con CHADS score >2
aneurisma ventricolo sinistro
trombosi del ventricolo sinistro
F.E. marcatamente depressa
embolia polmonare
Patients with atrial fibrillation
annual stroke risk without OAC
CHADS2 item
Congestive heart failure
Hypertension
Age ≥75
Diabetes
Previous stroke or
transient ischemic attack
Points
1
1
1
1
2
Rothberg et al Ann Intern Med. 2005; 143:241-250
TAO e duplice terapia antipiastrinica
Esperienza della Mayo-Clinic
66 Patients
No MACE
6 Patients with Readmission for Bleeding:
Bleeding from colon polyps, transfusion
Day 14
Hematuria secondary to urolithiasis Day 15
Peptic ulcer
Day 9
Groin haematoma
Day 2 (INR 1.0)
Nose bleeding
Minor ear bleeding
Orford JL et al., Am Heart J 2004
p = 0.2
p = 0.04
p = 0.3
% major bleeding
Gilard M et al. Am J Cardiol 2009;104:338-42
2.26% DES vs 1.19% BMS
p = 0.03
Ruiz-Nodar JM et al. Eur Heart J 2009;30:932-9
ANDREARUBBOLI1, JONATHAN L. HALPERIN2, K.E. JUHANIAIRAKSINEN3, MICHAEL BUERKE4, ERIC EECKHOUT5,
SAUL B. FREEDMAN6,ANTHONY H. GERSHLICK7,AXEL SCHLITT4, HUNG-FAT TSE8, FREEK W.A. VERHEUGT9 &
GREGORYY.H. LIP10
Orford JL et al. Am J Cardiol (2004)
Mattichak SL et al. J Interven Cardiol (2005)
Khurram Z et al. J Invasive Cardiol (2006)
Porter A et al. Catheter Cardiovasc Interv (2006)
Lip GYH & Karpha M. Chest (2006)
Karjalainen PP et al. Eur Heart J (2007)
DeEugenio D et al. Pharmacotherapy (2007)
Rubboli A et al. Coron Artery Dis (2007)
Nguyen MC et al. Eur Heart J (2007)
Wang TY et al. Am Heart J (2008)
Ruiz-Nodar JM et al. J Am Coll Cardiol (2008)
Rogacka R et al. J Am Coll Cardiol Intv (2008)
Ann Med 2008;40:428-36
Triplice terapia con TAO, ASA & tienopiridine vs. altri regimi:
meno stroke
&
più emorragie (maggiori)
(quanto più la terapia si prolunga)
Rubboli A et al. Ann Med 2008;40:428-36
Rossini R et al. Am J Cardiol 2008;102:1618-23
Raccomandazioni (livello evidenza C!!)
ACC/AHA/SCAI 2005 guideline update for
percutaneous coronary intervention
(J Am Coll Cardiol 2006;47:216- 235)
OAC+ASA+clopidogrel
ACC/AHA/ESC 2006 guidelines for the management
of patients with atrial fibrillation
(J Am Coll Cardiol 2006;48:854- 906)
OAC+clopidogrel
Guidelines on the management of valvular
heart disease
(Eur Heart J 2007;28:230- 268)
OAC+ASA+clopidogrel
Anticoagulants in heart disease: current status
and perspectives
(Eur Heart J 2007;28:880- 913)
OAC+ASA+clopidogrel
Management of acute myocardial infarction in patients
presenting with persistent ST-segment elevation
(Eur Heart J 2008;29:2909-45)
OAC+ASA+clopidogrel
Thromb & Haemost 2010;103:13-28
Triplice terapia (TAO + ASA + clopidogrel):
indicata nei pz. a rischio TE medio-elevato dopo impianto di stent
(verosimilmente) associata ad aumentato rischio emorragico
da condurre con INR ai limiti inferiori del range terapeutico
da protrarre per il più breve tempo possibile , e quindi no stent medicati
Grazie per l'attenzione
Prevention of Premature Discontinuation of Dual Antiplatelet
Therapy in Patients With Coronary Artery Stents: Factors
Related to Premature Cessation of Thienopyridine Therapy
• Antiplatelet therapy may be stopped at the instruction of
physicians, dentists, and other healthcare providers who
are to perform an invasive or surgical procedure on the
patient because of misguided concerns about excessive
procedure-related bleeding.
• Many of these procedures (e.g., minor surgery, teeth
cleaning, and tooth extraction) can likely be performed at
no or only minor risk of bleeding or could be delayed
until the prescribed antiplatelet regimen is completed.
57
Grines CL, et al. Circulation. 2007 Jan:1-6.
Prevention of Premature Discontinuation of Dual
Antiplatelet Therapy in Patients With Coronary
Artery Stents: Need for New Recommendations:
Advisory Group’s Recommendations
Elective procedures for which there is significant
risk of peri- or post-operative bleeding should be
deferred until patients have completed an
appropriate course of thienopyridine therapy.
For DES patients who are to undergo subsequent
procedures that require discontinuation of
thienopyridine therapy, aspirin should be
continued if at all possible and thienopyridine
restarted as soon as possible.
•
58
Grines CL, et al. Circulation. 2007 Jan:1-6.
GESTIONE DELLA TERAPIA ANTIPIASTRINICA
Condizioni ad alto rischio di trombosi

nei primi 12 mesi dopo PTCA + stent medicato
 prima di 6 settimane da PTCA + stent non medicato
 prima di 2 settimane da PTCA senza stent
 infarto miocardico acuto (<7 gg) o recente (<30 gg)
 sindrome coronarica acuta

anatomia coronarica ad alto rischio
GESTIONE DELLA TERAPIA ANTIPIASTRINICA
IN CHIRURGIA
PRINCIPLE-TIMI 44
201 patients undergoing elective PCI
were randomized to prasugrel (n = 102) or high-dose
clopidogrel (n = 99)
At various follow-up points, mean inhibition of platelet
aggregation as assessed by light-transmission aggregometry
was impacted by PPI use in patients taking either of the 2
drugs, although the difference was not statistically significant
for most comparisons
PRINCIPLE-TIMI 44
Clopidogrel: Mean Inhibition of Platelet Aggregation
With PPI
Without PPI
Value
0.5 Hours
4.9 ± 16.1
4.9 ± 12.0
0.98
2 Hours
10.4 ± 16.2
24.2 ± 20.5
0.003
6 Hours (a)
18-24 Hours
23.2 ± 19.5
23.8 ± 14.4
35.2 ± 20.9
36.1 ± 20.8
0.02
0.03
TRITON-TIMI 38
(TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet
inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction)
randomized 13,608 patients with ACS undergoing PCI to receive
either prasugrel (loading dose of 10 mg, daily maintenance dose of 10
mg) or clopidogrel (loading dose of 300 mg, daily maintenance dose
of
mg) inanalysis
additionfocused
to aspirin.
PPI4,529
use was
at physician
discretion.
The75current
on the
patients
(33%) who
were
taking a PPI at the time of randomization. Dr. O’Donoghue and
colleagues found no association over the course of long-term followup between PPI use and the combined risk of cardiovascular death,
MI, and stroke in subjects assigned to clopidogrel (HR 0.94; 95% CI,
0.80-1.11) or prasugrel (HR 1.00; 95% CI, 0.84-1.20). Adjustment for
potential cofounders and the propensity to treat with a PPI did not
alter the findings.
August 31 at the European Society of Cardiology (ESC) Congress 2009
COGENT
To determine whether PPI versus placebo reduced important GI events in
patients on dual antiplatelet therapy
To determine if there was any cardiovascular interaction between clopidogrel
and PPI
Multicenter, international, randomized, double-blind, double-dummy, placebocontrolled, parallel group, phase 3 efficacy and safety study of CGT-2168, a
fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg),
compared with clopidogrel
The cardiovascular endpoint was the composite of cardiovascular death, nonfatal MI, CABG or PCI, or ischemic stroke.
The GI endpoint was upper GI bleeding, bleeding of presumed occult GI origin
with decrease in hemoglobin of ≥2 g/dL or decrease in hematocrit ≥10%,
symptomatic gastroduodenal ulcer confirmed by endoscopy orradiography, pain
of presumed GI origin with underlying multipleerosive disease confirmed by
endoscopy, obstruction, or perforation.
•
COGEN
T
The first, randomized assessment of clopidogrel and PPIson clinical
events
•The data provide strong reassurance that there is no clinically
relevant adverse cardiovascular interaction between clopidogrel and
PPIs
•The results call into question the exact relationship between ex
vivoplatelet assays and clinical outcomes, especially with respect to
assessing druginteractions–Platelet assays and observational data
are not a substitute for RCT data
•Further research is needed to define the optimal strategy to reduce
GI events in patients on antithrombotictherapy, though prophylactic
PPIsseem very promising
Interazioni
tienopiridine - inibitori pompa protonica
Clopidogrel and prasugrel are both prodrugs
metabolized by the cytochrome p450 enzyme system
(CYP3A4 and CYP2C19)
PPIs could possibly interfere with this metabolism,
or they might reduce absorption of the
thienopyridines by lowering gastric acidity,