Επιλογή αντιθρομβωτικής αγωγής σε επεμβάσεις στις καρωτίδες και τα περιφερικά αγγεία

Επιλογή αντιθρομβωτικής αγωγής σε επεμβάσεις στις καρωτίδες και τα περιφερικά αγγεία Μ. Ματσάγκας, MD, PhD, FEBVS Αναπλ. Καθηγητής

Aθηροσκλήρωση και Αθηροθρόμβωση Αθηροθρόμβωσ η = αθηροσκλήρωσ η με επισυμβαίνου σα θρόμβωση.

Αθηροθρόμβωση Θρόμβος που αποφράσσει πλήρως μ

Η καταστροφή της αθηρωματικής πλάκας οδηγεί σε αθηροθρομβωτικό σύμβαμα ΑΙΜΑΤ ΙΚΗ ΡΟΗ ΕΝΕΡΓΟΠΟΙΗ ΜΕΝΑ ΑΙΜΟΠΕΤΑΛΙ ΙΝΩΔΕΣ Α Adapted from: Falk E et al. Circulation 1995; 92: 657 71. MΑΚΡΟΦΑ ΓΑ ΙΣΤΙΚΟΣ ΠΑΡΑΓΟΝ ΤΑΣ

Παθολογική εξέλιξη αθηρωμάτωσης Αθηροσκλ ήρωση Θρόμβω ση ασταθής στηθάγχη ΟΕΜ ΑΕΕ κρίσιμη ισχαιμία άκρων καρδιαγγειακό ς θάνατος σταθερή στηθάγχη / διαλείπουσα χωλότητα «Ο άνθρωπος ζεί με την αθηρωμάτωση, πεθαίνει όμως από την θρόμβωση»

Η αθηροθρόμβωση συχνά προσβάλλει περισσότερες από μία αγγειακές κοίτες Προσβολή εξωκρανια κών εγκεφαλικώ ν αρτηριών 24.7% 7.4% 29.9% Ισχαιμική νόσος του μυοκαρδίου 3.3% 3.8% 11.8% 19.2% Περιφερική αρτηριακή νόσος *Data from CAPRIE study (n=19,185) [Coccheri S. Eur Heart J 1998; 19(suppl): p.1268]

Κλινικές εκδηλώσεις αθηροθρόμβωσης Νόσος των καρωτίδων Ασυμπτωματική Συμπτωματική Στεφανιαία νόσος Σπλαχνική αρτηριακή νόσος Νεφρο-αγγειακή νόσος Περιφερική αρτηριακή νόσος Ασυμπτωματική Διαλείπουσα χωλότητα Κρίσιμη ισχαιμία

Peripheral Artery Disease

Ο επιπολασμός της νόσου αυξάνει με την ηλικία Μελέτη Rotterdam (ΚΒΔΠ <0.9) 1 Μελέτη San Diego 2 Ασθενείς με ΠΑΝ (%) 60 50 40 30 20 10 0 55-59 60-64 65-69 70-74 75-79 80-84 85-89 Ομάδες ηλικιών (έτη) 1 Meijer WT et al. Arterioscler Thromb Vasc Biol 1998; 18: 185-192. 2.Criqui MH et al. Circulation 1985; 71: 510-515.

Patients with PAD are at greater risk of morbid cardiovascular events and death than amputation 100 Causes of death: 55% coronary artery disease 10% cerebrovascular disease 10% other vascular 25% non-vascular 80 Patients (%) 60 40 Survival Myocardial Infarction 20 Intervention 0 0 1 2 3 4 5 6 7 8 9 10 Time (years) Amputation Ouriel K. et al, Lancet, 2001

Αυξημένη θνητότητα σε ασθενείς με σοβαρού βαθμού ΠΑΝ 5ετής θνητότητα Ασθενείς (%) 50 45 40 35 30 25 20 15 10 5 0 15 38 44 48 Καρκίνος μαστού 1 Kαρκίνο ς παχ. εντέρου 1 ΠροχωρημένηNon-Hodgkin s ΠΑΝ 2 λέμφωμα 3 1. Criqui MH. Vasc Med 2001; 6 (suppl 1): 3 7. 2. McKenna M et al. Atherosclerosis 1991; 87: 119 28. 3. Ries LAG et al. (eds). SEER Cancer Statistics Review, 1973 1997. US: National Cancer Institute; 2000.

Περιφερική Αρτηριακή Νόσος Αιτίες θανάτου ασθενών με ΠΑΝ 18% 60% 10% 12% Στεφανιαία νόσος Άλλα αγγειακά νοσήματα Εγκεφαλική ισχαιμία Μη αγγειακά αίτια

Risk of death is increased in patients with both symptomatic and asymptomatic PAD 100 Survival (% of patients) 75 50 25 0 0 2 4 6 8 10 12 Year Normal subjects* Asymptomatic PAD Symptomatic PAD Severe symptomatic PAD Criqui MH et al. N Engl J Med, 1992

Antiplatelet therapy in PAD Antithrombotic Trialists Collaboration 2002 9.214 PAD patients 42 Clinical Trials 23% reduction in CV events (p = 0.004) Antithrombotic Trialists' Collaboration BMJ 2002;324;71 86

Aspirin in PAD Most guidelines recommend ASA in PAD patients to prevent CV events Data about ASA are almost indirect Direct data exist for other antiplatelet drugs Ticlopidine STIMS J Int Med, 1990 Picotamide ADEP Circulation, 1993 Clopidogrel CAPRIE Lancet, 1996 ASA has not obtained an FDA mark in the USA for PAD standing alone Cocceri S Buenos Aires 2005

Aspirin and PAD Meta analysis of 42 RCTs in patients with PAD Treatment with aspirin resulted in a statistically non-significant decrease in the primary end point of CV events Berger et al. JAMA 2009

CAPRIE: Efficacy of clopidogrel vs ASA in MI, ischemic stroke, or vascular death (N=19,185) Cumulative event rate (%) 16 12 8 Median follow-up = 1.91 years ASA 5.83% 5.32% Clopidogrel ASA Clopidogrel 8.7% Overall Relative Risk Reduction P= 0.045 4 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up Study subjects had either recent MI, recent ischemic stroke, or symptomatic peripheral arterial disease. CAPRIE Steering Committee. Lancet 1996

CAPRIE: Subgroup analysis Relative Risk Reduction RRR (%) Ce rebral ishemia (p/ys=12.033) p=0,26 CAD (p/ys 11.630) p=0,66 PAD (p/ys 11.592) p=0,0028 TOTAL (p/ys=35.155) p=0,043-60 -50-40 -30-20 -10 0 10 20 30 40 50 60 ASA better Clopidogrel better CAPRIE Steering Committee. Lancet 1996

American Diabetes Association Consensus Statement 2003: PAD in people with diabetes Patients with diabetes and PAD may benefit more by taking clopidogrel than ASA American Diabetes Association. Diabetes Care, 2003

CHARISMA: Overall Population Primary Efficacy Outcome (MI, Stroke, or CV Death) 8 Placebo + ASA* 7.3% 6 Clopidogrel + ASA* 6.8% Cumulative event rate (%) 4 2 RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 0 0 6 12 18 24 30 Months since randomization Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006

CHARISMA: Monotherapy or combination therapy? subgroup analysis: none of the subgroups showed a statistically signifiacant reduction with combination therapy

Monotherapy or combination therapy? Combination therapy is not beneficial to patients with PAD especially those not at particularly high risk of CV event Mohler et al. Catheter and Cardiovasc Interv 2009

Antiplatelet therapy + Oral anticoagulants in PAD patients WAVE trial: Antiplatelet Coumadin vs Antipatelet alone Efficacy (MI, Stroke, CV death) Safety (major bleeding) Warfarin Antiplatelet Vascular Evaluation Trial Investigators N Engl J Med 2007

9 th ACCP In patients aged 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75 100 mg/d) over no therapy for the primary prevention of cardiovascular events Grade 2B CHEST 2012; 141:669S 690S

9 th ACCP For secondary prevention of cardiovascular disease in patients with symptomatic PAD,we recommend long term aspirin (75 100 mg/d) or clopidogrel (75 mg/d) Grade 1Α We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD Grade 1B CHEST 2012; 141:669S 690S

Interventions in PAD The role of antiplatelet therapy during and after interventions for PAD Much more questions than answers!!

Antiplatelets and by pass surgery Antiplatelet therapy is associated with an overall positive effect on primary patency 12 months post-operatively Dörffler Melly J, et al. Cochrane Database Syst Review 2003

Antiplatelets for synthetic by pass grafts Meta-analysis: Antiplatelets improved infrainguinal prosthetic graft patency (81% vs 47 %, p= 0.00001) at one year Brown J, et al. Cochrane Database Syst Review 2008 Antiplatelets do improve the patency of infrainguinal prosthetic grafts and should be provided to all these patients unless otherwise contraindicated

Oral anticoagulants and by pass surgery The Dutch Bypass Oral Anticoagulants study reported a benefit of warfarin (target international normalized ratio 3.0-4.5) over ASA 80 mg/day for venous grafts in patients undergoing infrainguinal grafting (3.0% per year improved graft patency) Oral anticoagulation was associated with more bleeding (2-fold increase) Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study Group. Lancet 2000 The coumadins have not been widely accepted for this indication But, they are used quite frequently in cases that there is high risk of graft occlusion and limb loss

Do we need dual antiplatelet therapy in by pass surgery? Not for venous grafts, but maybe for prosthetic grafts CASPAR trial, J Vasc Surg 2010

CASPAR trial: Clopidogrel+ASA vs ASA alone in below the knee bypass surgery 2-4 days ASA 75 100 mg / day Clopidogrel 75mg / day R Double-blinded trial up to 193 events (event driven trial) Bypass operation 1 month ASA 75 100 mg / day 24 months Placebo 1 tabl / day

CASPAR trial: Clopidogrel+ASA vs ASA alone in below the knee bypass surgery The combination of clopidogrel+asa did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting Subgroup analysis suggests that clopidogrel+asa confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk CASPAR trial, J Vasc Surg 2010

Abdominal Aortic Aneurysm Open repair Patients with AAA should be on low-dose aspirin and this should be continued through the perioperative period Level 3b, Recommendation C F.L. Moll, et al. Eur J Vasc Endovasc Surg 2011; 41: S1- S58.

Peripheral Transluminal Angioplasty and Stenting rises more and more with time it s s about to replace open surgery in most vascular beds

PTA and Stenting has many advantages Minimal invasive approach Ability to treat the high-risk patients Ability to treat poor out-flow lesions Shorter hospital stay Revascularization using the native arteries No prosthetic grafts No harvesting of useful veins

but also some disadvantages and limitations Radiation and contrast media exposure Reduced long term patency More re-interventions Need for more intensive follow-up

Cost effectiveness No reliable data so far It depends on re-interventions prevention of re-stenosis / re-occlusion

Platelet activation Always during peripheral PTA even after just an angiography! Buchholz AM et al., Thrombosis Research, 2003

Platelet adhesion Is an important step in the development of neo- intima hyperplasia and subsequent re-stenosis In the site of stenting there is an increase in platelet deposition Cassar K et al., Eur J Vasc Endovasc Surg, 2003

Platelet aggregation Platelet recruitment and adhesion at the site of injury Platelet activation and aggregation

Fact We do need antiplatelet action during and after peripheral PTA and stenting

Antithrombotic therapy in peripheral PTA Few studies guide clinicians regarding type and duration of antithrombotic therapy following such procedures Current practice is very heterogeneous and often is based on indirect evidence from studies in patients undergoing coronary stenting Chest 2012; 141: e669s e690s

Antithrombotic therapy in peripheral PTA There are no RCTs comparing antithrombotic agents post PTA with stent placement Indeed, it remains unclear whether PTA with stent placement is superior to PTA alone with respect to patient important outcomes Nevertheless, stenting is performed very frequently!! Chest 2012; 141: e669s e690s

Antiplatelets vs oral anticoagulants in PTA Aspirin 50 to 330 mg, started before femoropopliteal endovascular treatment, appeared to be the most effective and safest strategy Reduced the incidence of re occlusion at 6 and 12 months when compared with no therapy or vitamin K antagonists Cohrane Database Syst Review 2005

Basic and acceptable principle We need antiplatelet therapy during and after peripheral PTA and Stenting!!

Questions to be answered Is there a need for more intensive therapy? If there is, what it should be? and for how long?

Statement It looks reasonable to consider the combination of two antilpatelet drugs during and after peripheral PTA and Stenting but Data are lacking!!

Dual antiplatelet therapy in PTA The Clopidogrel and Aspirin in the Management of Peripheral Endovascular Revascularization (CAMPER) study was started in the US to evaluate the efficacy and safety of this dual therapy after femoropopliteal PTA Unfortunately, the study was stopped because of insufficient randomization numbers Many patients were already treated off label with clopidogrel and aspirin Physicians were uncomfortable with patients receiving aspirin monotherapy after PTA Cohrane Database Syst Review 2012

The usual clinical practice up to date Dual combination therapy with aspirin (100 mg/d) and clopidogrel (75 mg/d) for 1 3 months after peripheral PTA and Stenting Tepe et al. N Eng J Med 2008

The main question remains un answered Dual or single antiplatelet therapy after peripheral PTA and Stenting? What the recent Guidelines tell us about?

9th ACCP Despite low quality evidence regarding thienopyridines in patients undergoing PTA with stent placement for PAD, many interventionists provide dual antiplatelet therapy for 1 to 3 months post PTA, particularly if a stent is placed in a small peripheral vessel The rationale for this practice is based on the results from coronary artery stenting trials Chest 2012; 141: e669s e690s

9th ACCP ACCP is skeptical about extrapolating these data to all patients with PAD given differences in the risk of stent thrombosis (lower in stenting of larger caliber peripheral arteries compared with smaller coronary arteries), difference in stent types, and differing outcomes related to stent thrombosis (limb ischemia vs MI) Given that dual antiplatelet therapy is associated with an increased risk of major bleeding compared with single antiplatelet therapy Chest 2012; 141: e669s e690s

9th ACCP recommendation 7.1. For patients undergoing peripheral artery percutaneous transluminal angioplasty (PTA) with or without stenting, we recommend long term aspirin (75 100 mg/day) or clopidogrel (75 mg/day) (Grade 1A). For patients undergoing peripheral artery PTA with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C) Chest 2012; 141: e669s e690s

9th ACCP 7.1. Comment Values and preferences: Patients who place a high value on an uncertain reduction in the risk of limb loss and a relatively low value on avoiding a potential increased risk of bleeding are likely to choose to use dual antiplatelet therapy Chest 2012; 141: e669s e690s

AHA 2011 update Guidelines for PAD Antiplatelet therapy is indicated to reduce the risk of MI, stroke, and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or critical limb ischemia, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia. Level of Evidence: A Rooke TW, et al. J Am Coll Cardiol. 2011; 58: 2020 45.

AHA 2011 update Guidelines for PAD The combination of aspirin and clopidogrel may be considered to reduce the risk of cardiovascular events in patients with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or critical limb ischemia, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia and who are not at increased risk of bleeding and who are at high perceived cardiovascular risk Level of Evidence: B Rooke TW, et al. J Am Coll Cardiol. 2011; 58: 2020 45.

ESVS 2011 Guidelines for Critical Limb Ischemia In line with recommendations for patients with coronary heart disease, an intermittent administration of dual antiplatelet therapy (aspirin plus clopidogrel) may be considered for patients undergoing stent implantation or drug eluting balloon angioplasty of femoropopliteal or infrapopliteal arteries. Level 5; Grade D N. Diehm, et al. Eur J Vasc Endovasc Surg 2011; 42(S2): S33 S42.

ESVS 2011 Guidelines for Critical Limb Ischemia After prosthetic bypass or endovascular revascularisation, ASA or ASA combined with dipyridamole, should be given daily at low dose (50 to 300 mg) to lower the incidence of bypass or angioplasty occlusions Level 1b; Grade B Additional use of thienopyridine (clopidogrel) may be beneficial without increasing the risk of major bleeding. Level 2b; Grade C F. Dick, et al. Eur J Vasc Endovasc Surg 2011; 42(S2): S75 S90.

Mono or dual antiplatelet therapy? The MIRROR study Mono (ASA) vs dual (ASA + clopidogrel) therapy before and after peripheral PTA and stenting Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Questions to be answered Discontinuing antiplatelet therapy before the procedure? It looks reasonable not to Minimal invasive procedures High risk CV patients

Questions to be answered Is there a need for more intensive therapy? If there is, what it should be? and for how long?

Questions to be answered It looks reasonable to consider the combination of two antilpatelet drugs during and after peripheral PTA and Stending but Data are lacking!!

Questions to be answered Is there a need for a loading dose? If there is, when? and how? Before the procedure? After the procedure? What drug and in what dose?

Loading Antiplatelet Dose in PAD patients A loading dose of Clopidogrel (300mg) inhibits platelet activation in PAD patients as early as 2 hours Matsagas et al, Clin Appl Thromb Hemost, 2003 some years later Data are still lacking!!

Questions to be answered What about of the use of GP IIb/IIIa inhibitors during and after the procedure? If there a need to use them? In which cases?

GP IIb/IIIa inhibitors in peripheral PTA and Stending One randomized study (98 patients 103 limbs with long segment femoropopliteal occlusions), demonstrated significant benefit in patients receiving abciximab, improving patency and functional outcome Dorffler Melly Jet al. Radiology 2005 Although More data are needed!!

Other considerable issues The indications of PTA and Stenting in peripheral vessels are rapidly changing TASC (2000) TASC II (2007) still changing.. more and more total occlusions now treated longer lesions subintimal technique, remote endarterectomy thus more atherothrombotic surface!!

Long peripheral PTA and Stenting

The use of Drug Eluting Stents (DES) in peripheral interventions Initial use in tibial arteries DEB in femoropopleteal lesions Siablis D et al., J Endovasc Ther, 2007 Tepe G, et al., NEJM, 2008 Better results? Risk for acute thrombosis?

Other considerable issues Expanding use of covered stents in peripheral vessels No data from the coronaries No data at all!!! Do we need intensive antiplatelet therapy? Do we need anticoagulants? Can we adapt data from surgical prosthetic grafts?

Abdominal Aortic Aneurysm Endovascular repair Patients with AAA should be on lowdose aspirin and this should be continued through the perioperative period Level 3b, Recommendation C F.L. Moll, et al. Eur J Vasc Endovasc Surg 2011; 41: S1 S58.

Resistance to anti-platelet therapy It is well known that some PAD patients show resistance to ASA Matsagas et al, Ann Vasc Surg 2002 Recently has been stated that some cardiovascular patients have resistance to Clopidogrel Papathanasiou et al, Hellenic J Cardiol 2007 should we evaluate patients before peripheral interventions for resistance to antiplatelet drugs?

Resistance to anti-platelet therapy in PAD It is well known that some PAD patients show resistance to Aspirin (up to 20%) Matsagas et al, Ann Vasc Surg 2002 Karnabatidis D. et al, Cardiovasc Intervent Radiol 2013

CAPRIE: Subgroup analysis Relative Risk Reduction RRR (%) Ce rebral ishemia (p/ys=12.033) p=0,26 CAD (p/ys 11.630) p=0,66 PAD (p/ys 11.592) p=0,0028 TOTAL (p/ys=35.155) p=0,043-60 -50-40 -30-20 -10 0 10 20 30 40 50 60 ASA better Clopidogrel better CAPRIE Steering Committee. Lancet 1996

Resistance to clopidogrel Despite the initial success rate of PTCA some pts suffered recurrent ischemic events despite dual antiplatelet treatment Low response to clopidogrel?

Peripheral Transluminal Angioplasty and Stenting Resistance to clopidogrel in peripheral PTA The MIRROR study Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Resistance to clopidogrel in peripheral PTA The MIRROR study RCT 80 patients (40 to each group) Loading dose prior to intervention 500mg aspirin + 300mg clopidogrel 500mg aspirin or Maintenance dose for 6 months after the intervention 100mg aspirin + 75mg clopidogrel or 100mg aspirin Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Resistance to clopidogrel in peripheral PTA The MIRROR study Primary endpoint was the rate of patient s resistant to clopidogrel Secondary endpoints included the clinical development 6 months after the intervention Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Resistance to clopidogrel in peripheral PTA The MIRROR study Mono (ASA) vs dual (ASA + clopidogrel) therapy before and after peripheral PTA and stenting Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Resistance to clopidogrel in peripheral PTA The MIRROR study 30% of patients who had received clopidogrel were resistant Two clopidogrel patients required reintervention and revascularisation Both were resistant to clopidogrel Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Resistance to clopidogrel in peripheral PTA The MIRROR study The results seem to support the use of dual antiplatelet therapy periinterventionally and for 6 months post interventionally after endovascular treatment of PAD patients An optimal loading dose and optimal duration of the medication are difficult to determine and recommend It might be reasonable to measure clopidogrel resistance before endovascular treatment of PAD patients, at least in anatomically complex procedures Tepe G, et al. Eur Radiol (2012) 22:1998 2006.

Clopidogrel responsiveness in PAD The PRECLOP Study Spiliopoulos et al, JACC 2013

Clopidogrel responsiveness in PAD The PRECLOP Study Prospective study 100 pts Rutherford stage 3-6 Succesfull infrainguinal angioplasty or stenting Dual antiplatelet 1 month prior - 6m post vs single with Clop 75mg during FU Clopidogrel responsiveness prior to the procedure Spiliopoulos et al, JACC 2013

Clopidogrel responsiveness in PAD The PRECLOP Study 1-year clinical events Death Bleeding Major amputation Target vessel re-intervention Platelet responsiveness to clopidogrel, expressed as platelet reactivity P2Y12 reactive units (PRU) Spiliopoulos et al, JACC 2013

Clopidogrel responsiveness in PAD The PRECLOP Study Events

Clinical adverse events p<0.001 Quartile distribution of on-treatment platelet responsiveness to clopidogrel and clinical events Spiliopoulos et al, JACC 2013

Prediction of major events at 1y PRU value 234 Sensitivity 92.1% Specificity 84.2% Spiliopoulos et al, JACC 2013

Event-free survival PRU value above the cutoff value of 234 was the only independent predictor of increased adverse clinical events, with an adjusted hazard ratio of 16.94 Spiliopoulos et al, JACC 2013

Event-free survival Quartile-Based Event-Free Survival Spiliopoulos et al, JACC 2013

Clopidogrel responsiveness in PAD The PRECLOP Study An inadequate response to clopidogrel, identified using point-ofcare testing just prior to the procedure, is a new strong independent predictor of reduced event-free survival, adversely influencing midterm clinical outcomes of peripheral angioplasty and stenting ROC analysis identified PRU >234 as the optimal cutoff value to predict clinical outcomes of infrainguinal angioplasty or stenting. This is in line with the majority of the coronary studies, as according to a recent meta-analysis, a PRU value >230 was associated with a significant twofold increased rate of the composite endpoint of death, myocardial infarction, and stent thrombosis Brar et al, JACC 2011 Spiliopoulos et al, JACC 2013

Initial Experience With Ticagrelor in Patients With Critical Limb Ischemia In patients with High On- Clopidogrel Platelet Reactivity Undergoing Complex Peripheral Endovascular Procedures Spiliopoulos et al, Cardiovasc Intervent Radiol 2014 Spiliopoulos et al, JACC 2013

Initial Experience With Ticagrelor in PAD 37 pts, 40 limbs Rutherford stage 4-6 High on clopidogrel platelet reactivity (HCPR). Platelet reaction units (PRU)>234 (VerifyNow P2Y12 assay) Dual antiplatelet ASA100mg + ticagrelor 180/90 mg twice daily Primary safety outcome: total major bleeding Primary efficacy outcome: the composite of cardiovascular death and major amputation Spiliopoulos et al, Cardiovasc Intervent Radiol 2014

Initial Experience With Ticagrelor in PAD No ticagrelor-related or other major complications were detected during follow-up In total, 4 periprocedural minor adverse events were noted (10.8%) Two patients (5.4%) discontinued ticagrelor intake due to reported minor adverse events Spiliopoulos et al, Cardiovasc Intervent Radiol 2014

Initial Experience With Ticagrelor in PAD Spiliopoulos et al, Cardiovasc Intervent Radiol 2014

Carotid Artery Disease Carotid Endarterectomy Carotid Artery Stenting

ΑΕΕ: υπεύθυνο για περίπου 10% της θνησιμότητας παγκοσμίως Diarrhoea Tuberculosis Malaria Perinatal causes Chronic obstructive pulmonary disease 5% 4% 3% 3% 2% 27% Other causes HIV/AIDS 5% Respiratory infections 7% Coronary heart disease 9% 13% Accidents Stroke 10% Cancer 12% American Stroke Association. Heart Disease and Stroke Statistics 2004

Νόσος των καρωτίδων Παθοφυσιο λογία Εμβολικός ο μηχανισμός πρόκλησης ΑΕΕ Μείωση αρτηριακής παροχής Μεγάλες στενώσει ς Αμφοτερό

Νόσος των καρωτίδων Η καρωτιδική στένωση θεωρείται υπεύθυνη για περίπου 20% των ΑΕΕ Η συχνότητα των ΑΕΕ που σχετίζονται με μια σημαντική καρωτιδική στένωση υπολογίζεται σε 1-2% ανά έτος Η επίπτωση κυμαίνεται από 0.2% σε άνδρες >50 ετών, μέχρι

Νόσος των καρωτίδων

Νόσος των καρωτίδων Διάγνωση Αγγειογρα φία Χρυσός κανόνας Διαφορές μεταξύ NASCET και ECST Έγχρωμο duplex Υπερηχογρ αφικά κριτήρια

Σημασία της υφής της αθηρωματικής πλάκας Η υφή της πλάκας σημαντικός παράγοντας πρόκλησης ΑΕΕ Απλές ινώδεις πλάκες μικρός κίνδυνος ΑΕΕ Επιπλεγμένες πλάκες (ενδοπλακική αιμορραγία, εξέλκωση) μεγάλος κίνδυνος ΑΕΕ Υπερηχογραφικός χαρακτηρισμός Υπερηχογενείς μικρός κίνδυνος ΑΕΕ Υποηχοϊκές μεγάλος κίνδυνος ΑΕΕ Ανάλυση ηχογένειας Μέτρηση ηχογένειας Ανάπτυξη

Ενδείξεις αντιμετώπισης Συμπτωματικοί ασθενείς ΑΕΕ ΠΑΡΟΔΙΚΟ Διάρκεια <24h ΑΝΑΣΤΡΕΨΙΜΟ Διάρκεια >30 ημερών ΑΥΞΑΝΟΜΕΝΗΣ ΕΝΤΑΣΗΣ (Crescento TIA) ΠΛΗΡΕΣ Παροδική αμαύρωση Βέλτιστη συντηρητική αγωγή Επεμβατική αντιμετώπιση Στένωση > 70% Στένωση 50-70% (υπό προϋποθέσεις)

Ενδείξεις αντιμετώπισης Ασυμπτωματικοί ασθενείς Βέλτιστη συντηρητική αγωγή Επεμβατική αντιμετώπιση Στένωση > 80%?

9 th ACCP: Antiplatelet treatment in Asymptomatic Carotid patients 9.1. For persons with asymptomatic carotid stenosis, we suggest aspirin 75 to 100 mg daily over no aspirin therapy Grade 2B CHEST 2012; 141:669S 690S

9 th ACCP: Antiplatelet treatment in Symptomatic Carotid patients 9.2 9.3. In patients with symptomatic carotid stenosis (including recent carotid endarterectomy), we recommend long term antiplatelet therapy with clopidogrel (75 mg once daily) or aspirinextended release dipyridamole (25 mg/200 mg bid) or aspirin (75 100 mg once daily) over no antiplatelet therapy Grade 1A We suggest either clopidogrel (75 mg once daily) or aspirinextendedrelease dipyridamole (25 mg/200 mg bid) over aspirin (75 100 mg) Grade 2B CHEST 2012; 141:669S 690S

MATCH: Combination of ASA+Clopidogrel vs Clopidogrel in high risk recently symptomatic patients Clopidogrel 75 mg o.d. + ASA 75 mg o.d. n=3.793 Mean time From event to radomization: 26,5 ημέρες R Clopidogrel 75 mg o.d. + placebo 1 tab o.d. n=3.793 Ημέρα 1 Σε ένα Μήνα Σε 3 Μήνες Σε 6 Μήνες Σε 12 Μήνες Σε 18 Μήνες - Diener HC et al, Lancet 2004

MATCH trial ASA additional to Clopidogrel Efficacy (MI,stroke, CV death, readmission) Safety Primary intracranial heamorrage RRR= 6,4% P=0,244 P=0,029

Καρωτιδική ενδαρτηρεκτομή Τεχνικές Επιμήκης αρτηριοτομή - ανάστροφη ενδαρτηρεκτομή Τοποθέτηση εμβαλώματος ; Προστασία του εγκεφάλου Προσωρινή παράκαμψη ; Διεγχειρητική αναισθησιολογική φροντίδα Γενική - τοπική αναισθησία Αιμοδυναμικός έλεγχος Διεγχειρητικός έλεγχος εγκεφαλικής λειτουργίας Μέτρηση πιέσεως αποκλεισμού

Καρωτιδική ενδαρτηρεκτομή Μετεγχειρη τική φροντίδα Διαταραχές ΑΠ το 1ο 24ωρο Σύνδρομο επαναιμάτωσ ης Έξοδος ασθενούς 2η-3η μτχ. ημέρα Επιπλοκές ΑΕΕ Κάκωση κρανιακών

Καρωτιδική ενδαρτηρεκτομή

Ενδοαυλική αντιμετώπιση (stenting καρωτίδος) Αρχικός ενθουσιασμός Μικρές σειρές με καλά αποτελέσματα Όχι ανάλογη συνέχεια ΑΕΕ περίπου 8% (meta-analysis, Stroke 2000) Ανάπτυξη συστημάτων προστασίας του εγκεφάλου Προοπτικές πολυκεντρικές μελέτες σύγκρισης ενδαρτηρεκτομής και αγγειοπλαστικής Αμφιλεγόμενα και αντικρουόμενα αποτελέσματα Εφαρμογή αγγειοπλαστικής (American Heart Association)

Ενδοαυλική αντιμετώπιση (stenting καρωτίδος)

Interventions in Carotid Artery Disease The role of antiplatelet therapy during and after interventions for Carotids A lot of questions, few answers!!

Antiplatelets and Carotid Endarterectomy (CEA) Antiplatelets reduce the odds of stroke in patients undergoing CEA Engelter S, et al. Cohrane Syst review 2003 Aspirin at a dose of 75 325 mg daily should be given before, during and following CEA Grade A Liapis C, et al. ESVS Guidelines 2009 9 th ACCP, CHEST 2012; 141:669S 690S

Clopidogrel and CEA More data from randomized trials are required to establish the role of clopidogrel during CEA Liapis C, et al. ESVS Guidelines 2009

Dual antiplatelet therapy and CEA There are not enough data at the moment, but

Dual antiplatelet therapy and CEA However, there are still questions Continue the dual therapy? For how long?

Dual antiplatelet therapy and CEA Safety issues to be addressed first Risk of wound hematoma at carotid endarterectomy under dual antiplatelet therapy Oldag A. et al, Langenbecks Arch Surg 2012

Dual antiplatelet therapy and CEA 684 pts underwent CEA 15-years period Wound hematoma (any) Aspirin 48 of 410 (11.7%) Clopidogrel 33 of 162 (20.4%) Dual therapy 27 of 112 (24.1%) Severe space-occupying hematoma needing operative reexploration Aspirin 5 of 410 (1.2%) Clopidogrel 7 of 162 (4.3%) Dual therapy 4 of 112 (3.6%) Oldag A. et al, Langenbecks Arch Surg 2012

Dual antiplatelet therapy and CEA Oldag A. et al, Langenbecks Arch Surg 2012

Dual antiplatelet therapy and CEA Safety issues to be addressed Risk of postoperative bleeding Hale B. et al, Vascular 2013

Dual antiplatelet therapy and CEA 1472 pts underwent CEA 7-years period Postoperative bleeding No therapy 1.2% Aspirin 0.9% Dual therapy 4.4 % Re-operation for bleeding No therapy 1.0% Aspirin 0.5% Dual therapy 2.5% Hale B. et al, Vascular 2013

Dual antiplatelet therapy and CEA Hale B. et al, Vascular 2013

Dual antiplatelet therapy and CEA Initial experience with DAPT during and after carotid endarterectomy Pilot safety study performing CEA under DAPT Peroulis M. et al, ALPIC 2014

Dual antiplatelet therapy and CEA 21 pts underwent CEA 2-years period All patients were under dual antiplatelet therapy Aspirin Clopidogrel 100mg 75mg One patient (4,8%) had a post-operative ispilateral neck hematoma without need of surgical intervention NO neurologic events Peroulis M. et al, ALPIC 2014

What about Carotid Artery Stenting (CAS)? The risk of acute thrombosis could become disabling or even fatal After procedure embolization could lead to serious neurologic complications We need intensive antithrombotic therapy We have to define what it would be

Dual or single drug antiplatelet therapy for CAS? 24 patients 23 patients 75 mg aspirin + 24h Heparin Vs 75 mg aspirin + loading dose 300 clopidogrel 6-12 h before Neurological complication 25% vs 0% Bleeding disorders McKevitt et al. Eur J Vasc Endovasc Surg 2005

Dual or single drug antiplatelet therapy for CAS? Was there a difference in antiplatelet therapy?

There were many significant differences overall but, as for antiplatelet treatment While

Antiplatelet therapy for CAS Current Guidelines

Antiplatelet therapy for CAS CAS should be performed under dual antiplatelet treatment with aspirin and clopidogrel Grade A Dual antiplatelet treatment should start before CAS and continue for 3 months after stenting Grade C Liapis C, et al. ESVS Guidelines 2009

AHA Guidelines for CAS Before and for a minimum of 30 days after CAS, dual antiplatelet therapy with aspirin (81 to 325 mg daily) plus clopidogrel (75 mg daily) is recommended Level of Evidence: C Brott TG, et al. J Am Coll Cardiol 2011

What about loading dose before CAS? There is not sufficient evidence for a loading dose of Clopidogrel Reference Bush et al. Ann Vasc Surg 2003 Bhat et al. J Invas Cardiol 2001 Loading dose Clopidogrel 150 mg X2 when starting 300mg (none before) Comments Not a Clinical Trial Observed data Heparin or IIb/IIIa inhibitor used too

And about GP IIb/IIIa inhibitors? The adjunctive use of GP IIb/IIIa fibrinogen receptor antagonist may further reduce periprocedural ischemic events in patients undergoing CAS In a nonrandomized study of 128 patients receiving adjunctive abciximab, there were fewer major ischemic events There was 1 delayed intracranial hemorrhage in the abciximab treated patients Kapadia SR, et al. Stroke 2001

More questions waiting for answers Do we need a loading dose with clopidogrel before CAS? What is the proper dose (300mg or 600mg)? How long before the procedure? How long the dual therapy would last after CAS? 1 month, 3 months, further on?

Clopidogrel resistance in CAS Patients to undergo CAS maybe clopidogrel nonresponders Clopidogrel dose adjustment González A, et al. J Vasc Surg 2014

Clopidogrel resistance in CAS Prospective study 214 pts underwent CAS under DAPT (ASA + Clop) 99 (46.3%) had high on treatment reactivity (OTR, clopidogrel non-responders, PRU>230) Randomly assigned to Clopidogrel 75 mg or Clopidogrel 150 mg Re-assessed in 30 days González A, et al. J Vasc Surg 2014

Clopidogrel resistance in CAS González A, et al. J Vasc Surg 2014

In Conclusion Antiplatelet therapy seems to be a cornerstone in treating patients with peripheral and carotid artery disease A lot of Knowledge has been added during the last two decades but there are still many questions waiting for an answer

In Conclusion We do need intensive antiplatelet therapy during and after peripheral and carotid interventions, especially endovascular ones We are lacking of reliable data to develop evidence based guidelines in many subjects and at the same time we are performing these operations more and more in the every day practice

In Conclusion Dual antiplatelet therapy seems to be adequate before and at least of 1 month after peripheral endovascular interventions We have now studies, even small ones, showing that dual antiplatelet therapy is superior in interventional treatment of patients with PAD

In Conclusion Clopidogrel resistance in a large number of PAD patients is more than concerning!! On treatment HPR is associated with markedly increased adverse clinical events in patients undergoing peripheral endovascular procedures Point of care clopidogrel assessment might be useful in individualizing antiplatelet therapy to attain superior clinical results First and promising use of ticagrelor in high ontreatment platelet reactivity PAD patients undergoing endovascular procedures

In Conclusion Many patients with carotid artery disease are nonresponders to clopidogrel. The double dose adjustment is not sufficient. Carotid endarterectomy safety under dual antiplatelet treatment is quite doubtful at the moment It has to be proved if dual treatment is efficacious as well

So We need data, reliable data from carefully designed randomized trials, in many subjects To develop evidence based guidelines in the future

In the meanwhile We have to develop guidelines for optimal antiplatelet therapy during and after peripheral and carotid PTA and Stenting Even if these will be based in Grade C (small studies) and Grade D (expert opinions) recommendations and also adapting data from the coronaries

Ελληνικές κατευθυντήριες οδηγίες Τσελέπης Α. και συν, Ελληνική

Επιλογή αντιθρομβωτικής αγωγής σε επεμβάσεις στις καρωτίδες και τα περιφερικά αγγεία Ερωτήσεις πολλαπλής επιλογής

1 η ερώτηση Σε συμπτωματικό ασθενή με περιφερική αρτηριακή νόσο στο στάδιο της διαλείπουσας χωλότητας, τι είδους αντιθρομβωτική αγωγή θα χορηγήσετε; 1. Ασπιρίνη 100 mg 2. Κλοπιδογρέλη 75 mg 3. Συνδυασμό ασπιρίνης κλοπιδογρέλης

4. Συνδυασμό ασπιρίνης - 2 η ερώτηση Σε ασυμπτωματικό ασθενή με στένωση καρωτίδων, και περιφερική αρτηριακή νόσο στο στάδιο της διαλείπουσας χωλότητας, τι είδους αντιθρομβωτική αγωγή θα χορηγήσετε; 1. Ασπιρίνη 100 mg 2. Ασπιρίνη 325 mg 3. Κλοπιδογρέλη 75 mg

3 η ερώτηση Σε ασυμπτωματικό ασθενή με στένωση καρωτίδων, που υποβάλεται σε αγγειοπλαστική και stenting της καρωτίδας, τι είδους αντιθρομβωτική αγωγή θα χορηγήσετε; 1. Ασπιρίνη 100mg δια βίου 2. Ασπιρίνη 325mg για 1 μήνα και 100mg δια βίου στην συνέχεια 3. Κλοπιδογρέλη 75 mg δια βίου 4. Συνδυασμό ασπιρίνης

4 η ερώτηση Σε ασθενή με κρίσιμη ισχαιμία κάτω άκρων, που υποβάλεται σε αγγειοπλαστική και stenting της επιπολής μηριαίας αρτηρίας, τι είδους αντιθρομβωτική αγωγή θα χορηγήσετε; 1. Ασπιρίνη 100mg δια βίου 2. Κλοπιδογρέλη 75 mg δια βίου 3. Συνδυασμό ασπιρίνης κλοπιδογρέλης για 1 μήνα και κλοπιδογρέλης 75mg δια βίου στην συνέχεια