MEET Cannes 2007 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.