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Strategies to minimize complications in CAS
Periprocedural
medication:
what is a
must?
C. Tiefenbacher
Abt. Kardiologie, Angiologie, Pulmologie
Ruprecht-Karls-Universität Heidelberg
Medical therapy in patients undergoing CAS - why?
• to
prevent rapid thrombus formation and potential
embolization
• to prevent ischemic atherothrombotic events in other vascular
beds:
asymptomatic 75% carotid stenosis: annual stroke risk: 1.3%
combined risk of cardiac ischemia and vascular death: 10%
Lifelong management of risk factors:
Lifestyle: smoking cessation, healthy diet, exercise, weight
reduction
Drugs: hypertension, hypercholesterolemia, diabetes
Medication
• For CAS
Secondary prevention:
ACEI, ARB, Statins, ASS, Clopidogrel
• For STENTing
ASS, Clopidogrel, GPIIbIIIa inhibitors,
Heparin, Atropin
Why antiplatelet therapy?
During PCI:
• Intimal injury
release of procoagulant tissue factors,
exposure of platelet-adhesive proteins,
triggering formation of a platelet-rich thrombus
that seals the site of injury.
• distal microembolism after CA intervention
indicative of increased platelet reactivity to ADP
and increased systemic inflammation.
Following PCI:
• neointimal hyperplasia as late (typically >30 days after stent placement)
sequela of stenting.
• vascular inflammatory response after carotid stent implantation
determined by acute-phase reactants measurement is associated with 6month patency
adapted from O’Rourke et al CMAJ. 2004; 170: 1123–1133
Inhibition of platelet aggregation
arachidonic
acid
collagen
ASS
adrenalin
thrombin
fibrin
ADP
Clopidogrel
Ticlopidin
platelet
aggregation
GP IIb/IIIa
inhibitors
ASS
• effective antiplatelet
agent
• platelet response to aspirin shows marked
interpatient variability, some patients appear to
be aspirin resistant
Effect of ASS on vascular event rates
events in %
trials
therapy
control
previous MI
12
13,5
17
acute MI
15
10,4
14,2
previousstroke, TIA
21
17,8
21,4
Acute stroke
7
8,2
9,1
High risk
140
8
10,2
subtotal, without stroke
188
11,7
14,8
All
195
10,7
13,2
0
0,5
therapy better
1,0
1,5
therapy worse
BMJ 2002, 324:71-86
Clopidogrel versus ASS
16
12
ASS
MACE (%)
8
4
Clopidogrel
p = 0.043, n = 19,185
0
0
3
6
9
12
15
18 21
Monate
24
27
30
CAPRIE-population: MI, stroke, pAOD
33
36
Cochrane Review:
ADP-Receptor Antagonists vs ASA1
Cerebrovascular patients (n = 9,840)
Outcome
Odds ratio (and 95% CI)
Stroke (fatal or not)
14%
Myocardial infarction, stroke,
or vascular death
10%
0.6
0.8 1.0
ADP-blocker better
1. Hankey GJ et al. Stroke 2000; 31: 1779–84.
1.2
1.4
ASA better
CLOPIDOGREL + ASS
0.20
Placebo*
ASA*
MACE
0.16
0.12
RRR: 6.4%
0.08
(p=0.244)
0.04
0.00
0
3
6
9
12
15
18
months
MATCH: clopidogrel plus ASS vs clopidogrel alone in highrisk patients (n=7599) with recent TIA or ischemic stroke.
Significantly more major and minor bleedings in the
combination group. Incidence of life-threatening bleedings
higher in the combination group (2.6% vs 1.3%; p<0.001).
LANCET 2004;364:331-37
CAS: ASS + clopidogrel / + heparin?
•
CARESS: 108 pt with recent stroke or TIA: clopidogrel+ASS reduced
incidence of microemboli by 25% (1d) and 37% ( 7d) compared with ASS.
Circulation 2005; 111: 2233–2240
No increase in major bleeding.
•
n= 47, CAS: ASS+clopidogrel reduced 30d adverse neurological outcomes
after carotid stenting vs ASS+heparin (0% vs 25%; p=0.02); No increase in
bleeding complications. Unacceptable level of complications in the
ASS+heparin group resulted in the premature termination of the study in
Eur J Vasc Endovasc Surg 2005; 29: 522–527
favor of clopidogrel+ASS.
•
Carotid stent registry (n=162; 30d rate of ischemic events 5.6% in patients
with dual antiplatelet therapy; 1 /5 pt who did not receive an ADP antagonist:
in-stent thrombosis. 30-d rate of ischemic events higher in ticlopidine than
clopidogrel (13% vs 4.3%). Dual antiplatelet therapy did not increase
incidence of intracranial hemorrhage. J Inv Cardiol 2001;13:767–71
•
Case reports: fatal strokes in carotid stent patients who did not receive dual
Stroke 2001; 32: 2700–2702
antiplatelet therapy.
carotid artery stenting: ASS+clopidogrel
GPIIb/IIIa inhibitor – pro:
•
n=128, abciximab /placebo 12 hr before stenting, ASS+ clopidogrel /
ticlopidine after stentings
Procedural event rate lower in the abciximab-treated group (1.6%vs 8%)
New periprocedural events in the first 30d after discharge lower in
abciximab-treated group (8% vs 4.5%)
Stroke 2001;32:2328-32
•
n=100, clopidogrel + ASS+ heparin vs + adjunct bolus and
12h infusion of abciximab vs + filter protection:
abciximab did not significantly reduce the incidence of peri-interventional
ischemic events (10% versus 23%; P=0.2) and de novo ischemic lesions
(30% versus 47%; P=0.17) Significant reduction with filter protection
(P=0.023) TIAs less frequently with adjunct abciximab (P=0.05) compared
with standard antithrombotic therapy.
Stroke 2003;34:2560-67
GPIIb/IIIa inhibitor- con:
Retrospective review of 550 patients after CASS:
• GPIIb/IIIa inhibitors + heparin significantly increased the
30-day incidence of the composite end point of all stroke
and neurological death compared with heparin alone
(6.6% versus 2.4%; p=0.04).
• Increased intracranial and extracranial hemorrhage
events in the GPIIb/IIIa inhibitors plus heparin group, but
none were reported in heparin alone group.
• Conclusion: use of GPIIb/IIIa inhibitors and heparin in
carotid stenting should be discouraged.
J Endovasc Ther. 2003; 10: 33–41
Am J Cardiol 2005; 95:791- 95
Atropin
Prevention of angioplasty- and stent-induced
- bradycardia (up to 33%)
- hypotension (up to 50%)
more frequently in patients with primary CAS!!
Reduction of
- need of a vasopressor (up to 30%)
- cardiac morbidity (up to 15%)
Current recommendations
Preprocedurally
• Treatment of atherosclerosis: statins, ACE inhibitors, AT1-blocker…
• ASS 100mg/d
• Clopidogrel 75mg/d, starting at least 3days before the procedure
Intraprocedurally
• Heparin, ATT >300
• Atropin
Postprocedurally
• ASS 100mg/d
• Clopidogrel 75mg/d for at least 4 weeks
ASS + clopidogrel in carotid endarterectomy?
• For patients undergoing CE, aspirin 81 to 325 mg is
recommended (Aspirin and Carotid Endarterectomy
(ACE) trial
Lancet 1999; 353: 2179–2184
• Randomization of n=100 pt on ASS to concomitant
clopidogrel (n=46) or placebo (n=54) before CE.
Clopidogrel and ASS reduced the platelet response to
ADP by 8.8% while conferring a 10-fold reduction in the
relative risk of those patients having >20 emboli in the
postoperative period. No increased risk of bleeding
Circulation 2004; 109: 1476–1481
complications.
Studie
Design
RRR ( combined outcome for
stroke, MI, vasc. death)
ASS
ATC
n=18270
Clopidogrel
ASS vs.
Placebo/untreated
pts.
CAPRIE Clopi vs. ASS
22%
Meta-analysis of 21 trials
NS
MATCH:
increase of major (2
vs.1%) and life-thr. (2,6
vs.1,3%) bleeding;
p<0,001
n=6431
MATCH
Clopi vs. ASS+Clopi
NS
Ticlo vs. Placebo
23%
Ticlo vs. ASS
NS
ASS vs. Placebo
Dip vs. Placebo
ASS+Dip vs. Placebo
18%
16%
37%
n=7599
Ticlopidin
CATS
n=1072
TASS
~ 2% severe
hematologic adverse
events
n=3069
Dipyridamol ESPS-2
n=6602
Komb. vs. ASS um 23%
besser
Komb. vs. Dip um 25%
besser
ACI stenosis >70%
ASS + Clopidogrel
Resistenzbestimmung
∅ ASS-R
∅ Clopi-R
42%
ASS–R**
33%
kinetisch 50%
dynamisch 50%
Clopi–R**
25%
kinetisch 100%
* ASS-compliant
** Keine Koinzidenz von ASS-R und Clopi-R
Emboliedetektion
Normal
HIT
Artefakt
Aspirin/Clopidogrel-resistence in
Patients with stroke
ASS Resistenz
Clopidogrel
–Resistenz
Kollektiv (n)
Präv Repr. Klinische
.
Relevanz
stroke (82)
36%
+
stroke (306)
33%
-
Helgason;
Stroke 1994
stroke (291)
11%
-
Berrouschot;
Acta Neurol
Scand 2005
10 fach erhöhtes
Risiko für stroke/
MI/vasc. death
(FU 2y)
Literatur
Grotemeyer;
Thromb Res
1991 + 1993
cerebrovascula
r disease (129)
Alberts;
Stroke 2004
stroke,
PTCA/Stent
Herzinsuffizienz
(20/544)
Serebruany;
JACC 2005
Therapie der Carotisstenose
Protection devices
Präinterventionelle Therapie
Operation: ASS 100mg/die (oder Clopidogrel 75mg).
ASS + Clopidogrel vor elektiven Eingriffen absetzen.
PTA: ASS 100mg + Clopidogrel 75mg für mind. 3 Tage
Postinterventionelle Therapie
ASS u./o. Clopidogrel
Statine: bei LDL>130mg/dl, wenn + KHK ab LDL >100mg/dl.
Kein bestimmtes Statin, Dosisadjustierung an den
genannten Grenzen
ACE-Hemmer: symptomatische Patienten ACE-Hemmer
oder AT1-Blocker. Asymptomatische Patienten nur bei
Hypertonie.
`