ANTIAGGREGAZIONE PIASTRINICA

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1 ANTIAGGREGAZIONE PIASTRINICA NELLA PREVENZIONE DELL ICTUS Dott. Gino Volpi Pistoia, 12 Gennaio 2013

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3 Patologia dei grossi vasi Stenosi serrata Carotide interna

4 Patologia dei piccoli vasi: infarto lacunare: Infarti lacunari multipli di piccole dimensioni spesso asintomatici Legame stretto con l ipertensione

5 MALATTIA DEI PICCOLI VASI Infarto lacunare Patologia ischemica della sostanza bianca (leucoaraiosi) Emorragia cerebrale a sede tipica

6 ALTRE CAUSE DI STROKE Dissecazione vasi epiaortici Vasculite Coagulopatie-sindrome da antifosfolipidi (LAC, antcardiolipina) Malattie metaboliche Infarto emicranico Farmaci Altre

7 ICTUS: PREVENZIONE SECONDARIA Interventi mirati Endoarterectomia carotidea stenting in caso di stenosi sintomatica Anticoagulanti orali in caso di fibrillazione atriale. Gestione dei fattori di rischio Fumo, dieta. Esercizio fisico Ipertensione arteriosa Colesterolo Antiaggreganti

8 Antiaggreganti piastrinici: Inibitori del Tromboxano A2: Acetil salycilic acid ASA; Triflusal. Inibitori della fosfodiesterasi: Dipiridamolo; Cilostazolo. Antagonisti del recettore ADP: Ticlopidina, Clopidogrel, Prasugrel Inibitori della Ciclossigenaasi piastrinica: Indobufen, ASA Inibitori GP IIb-IIIa : Tirofibam, Lotrafibam Antagonistidel recettore del Tromboxano: Terutroban

9 Antiaggreganti Piastrinici CLOPIDOGREL C ADP ADP GPllb/llla (Fibrinogen receptor) Activation Collagen thrombin TXA 2 ASA COX TXA 2 COX (cyclo-oxygenase) ADP (adenosine diphosphate) TxA 2 (thromboxane A 2 ) 1. Schafer AI. Am J Med 1996; 101:

10 Efficacy of Antiplatelets in Prevention of Ischemic Events % of Patients Having Stroke, MI, or Vascular Death 25% 20% 15% 10% 5% 22% 29% 25% 32% Antiplatelet Therapy Control 27% 25% 0% Prior Stroke/TIA Acute MI Prior MI Other High High Risk Risk All Patients Antiplatelet Trialists Collaboration. BMJ. 1994;308(6921): PLA012c

11 Antithrombotic Trialists Collaboration: BMJ 2002; 324:71 8 La terapia antiaggregante dovrebbe essere considerata routinariamente per tutti I pazienti a rischio La terapia antiaggregante riduce eventi vascolari gravi in un ampio range di pz ad alto rischio: MI e stroke acuto MI stroke/tia pregressi CHD (i.d. angina instabile, scompenso cardiaco) PAD (i.d. claudicatio intermittent) Alto rischio embolico (i.d. fibrillazione atriale) Altri fattori ad alto rischio (e.g. diabete) 1 La terapia antiaggregante dovrebbbe essere mantenuta a lungo termine 11

12 ASPIRINA nella Prevenzione Primaria delle CVD In una metanalisi di 6 trial randomizzati sulla Prevenzione primaria, ASA produce una riduzione statisticamente significativa e clinicamente importante di circa 1/3 del rischio di primo infarto del miocardio ma non ci sono dati conclusivi disponibili sullo stroke e la morte cardiovascolare. Il rischio medio a 10 anni di un primo evento CHD fra questi uomini e donne apparentemente sani in 6 trial randomizzati è meno del 5%. Manca una evidenza in soggetti apparentemente sani il cui rischio a 10 anni di un primo event CHD sia del 10-19%. 19%. Fino ad allora ogni decisione sull uso di ASA in prevenzione primaria dovrebbe essere giudicata individualmente dal medico curante Per il momento le linee guida prevedono l uso di ASA in Prevenzione Primaria se il rischio a 10 anni è tra il 6% e il 10%. (Classe I Livello di evidenza A). Writing Group (Baigent C, Blackwell L, Buring J, Collins R, Emberson J, Godwin J, Hennekens C, Kearney P, Meade T, Patrono C, Peto R, Roncaglioni R, Zanchetti A). Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis analysis of individual participant data. Lancet. 2009;373:

13 Dosaggio Aspirina: confronto indiretto % Reduction Regimen No Trials (SE) 3P value Aspirin Alone (mg) (3) < (3) < (6) < < (8) NS Total (2) < Alcuni Autori riportano una minor efficacia della forma a protezione enterica In caso di intervento chirurgico stop 5 gg prima e go 48 ore dopo (come Clopid..). AntiThrombotic Trialists Collaboration. Lancet, 2002

14 Confronto Indiretto e Diretto fra dosi giornaliere di Aspirina di 325 mg o meno ed emorragie extracraniche maggiori nei Trial di Prevenzione Secondaria Confronto indiretto: : Nellla metanalisi dei Trial con dosi di aspirina di 325 mg o meno ( , , or <75), il rischio di emorragie maggiori extracraniche era simile. Confronto Diretto: : Nei due Trial che hanno confrontato direttamente dosi di aspirina di mg contro <75mg, il rischio di emorragie maggiori extracraniche era simile. AntiThrombotic Trialists Collaboration. Lancet, 2002

15 Elevato uso di antiaggreganti piastrinici in atto in pazienti con stroke 1,582 patients admitted with new or recurrent ischaemic stoke Other antiplatelet drug (1%) ASA + other antiplatelet drug (1%) No antiplatelet medication 60% 31% ASA alone ASA + clopidogrel (2%) Clopidogrel alone (4%) Nearly a third of admissions for ischaemic stroke may represent a failure of ASA monotherapy 1.Qureshi et al. Pharmacotherapy 2006;26:

16 Registro REACH: farmaci e nuovi eventi CV Athugh 62 % f CVD patiets were ASA at baseie there was sti a high 1 year evet rate 1-Year Event Rate % * CVD = cerebrovascular disease Population at risk in the REACH Registry 1. Bhatt DL, et al. JAMA Jan 11;295(2): Steg G et al. JAMA 2007;297:

17 POSSIBILI CAUSE DI RECIDIVA DI ICTUS IN CORSO DI TERAPIA CON ASA PATOGENESI NON ATEROTROMBOTICA (ictus embolico, arterite,ipercogulabilità) INADEGUATEZZA DEL CONTROLLO DI ALTRI FATTTORI DI RISCHIO RIDOTTA BIODISPONIBILITA DI ASA (scarsa compliance porta ad incremento del 40% di eventi vascolari maggiori, basse dosi, trattamento con Ibuprofene, Naproxene) VIE ALTERNATIVE DI ATTIVAZIONE PIASTRINICA (20% nonresponsiveness to ASA Gengo et al 2008) TURNOVER PIASTRINICO ELEVATO (Risposta allo stress) POLIMORFISMO GENETICO ( mutazione della COX1 o del complesso recettoriale IIb/IIIa) (mutazione o competizione con inibitori di pompa del gene P2Y12 che metabolizza clopidogrel nel metabolita attivo inibitore del recettore piastrinico dell ADP).

18 Warfarin Aspirin Recurrent Stroke Study (WARSS) 2200 ictus ischemici non cardioembolici > 50% occlusivi dei piccoli vasi Warfarin INR v. ASA 325 mg Nessuna differenza negli eventi (con trend a favore di ASA) Lieve trend in favore di warfarin nei cryptogenetici Nessuna differenza: Ab anticardiolipina, PFO Warfarin: limitate indicazioni stroke Mohr J, et al, for the WARSS Group. N Engl J Med. 2001;345:

19 Warfarin-Aspirin for Recurrent Probability of Event (%) Stroke Study (WARSS) Warfarin Aspirin Days after Randomization Number at Risk Warfarin Aspirin Mohr J, et al, for the WARSS Group. N Engl J Med. 2001;345:

20 WASID study: Warfarin and Probability of Primary End Point Aspirin in Symptomatic Intracranial Diseases 0.4 p=0.83 Aspirin 0.3 Warfarin Probability of Event (%) Warfarin Aspirin Years after Randomisation Days after Randomisation No. at risk Aspirin Warfarin No. at risk Warfarin 1,1031,047 1, Aspirin 1,1031,057 1,032 1, Primary endpoint: Stroke and death Death 1. Chimowitz MI et al. N Engl J Med 2005;352:

21 WASID study: Warfarin and Aspirin in Symptomatic Intracranial Diseases Probability of Major Haemorrhage 0.4 p= Warfarin 0.1 Aspirin Years after Randomisation No. at risk Aspirin Warfarin Major haemorrhages No. NR of Categ ory patien t yr Major Haemorrhage No. of eve nts No. of No. events of per 100 eve patient-yr nts (95% CI) Ischaemic Stroke No. of events per 100 patient-yr (95% CI) 24.9 (15.8- Major Cardiac Events No. No. of of events eve nts per 100 patient-yr (95% CI) 1.1 ( (5.2- < ) 19.9) 37.3) ( ( ( ) 8.7) 2.2) ( ( ( ) 16.7) 16.7) INR versus recurrent stroke 20.6 and (0.5- haemorrhage (0-61.6) 114.5) ( ) 1. Chimowitz MI et al. N Engl J Med 2005;352:

22 CAPRIE: Long-Term Efficacy of Clopidogrel versus ASA 1 Population (1/3 MI; 1/3 stroke;1/3 PAD) Cumulative Event Rate (Myocardial Infarction, Ischemic Stroke or Vascular Death) Cumulative event rate (%) ASA Clopidogrel p = 0.043, n = 19, % * Overall relative risk reduction Months of follow-up ASA = acetylsalicylic acid MI = myocardial infarction *Intention to treat analysis 1.CAPRIE Steering Committee. Lancet 1996; 348: Antiplatelet Trialists' Collaboration. BMJ 2002; 324:

23 CAPRIE: Maggior beneficio in pazienti ad alto rischio vascolare Events Prevented/1,000 Patients/Year over ASA Event rate * /1000 patients (average follow- -up, 2 years) ASA Clopidogrel 0 All CAPRIE patients¹ (n=19,825) Prior history of any Prior history of major ischemic event² acute event (MI or stroke) 3 (n=8,854) (n=4,496) *Event rate of myocardial infarction, ischemic stroke, or vascular death 1. CAPRIE Steering Committee. Lancet 1996; 348: Jarvis B, Simpson K. Drugs 2000; 60: Ringleb PA et al. Eur Heart J 1999; 20: 666.

24 CAPRIE: Magggior beneficio nei Diabetici Events Prevented/1,000 Patients/Year over ASA Event rate * /1000 patients/year ASA Clopidogrel 0 All CAPRIE patients¹ Diabetes² Diabetes treated with insulin² *Event rate of myocardial infarction, stroke, vascular death, or hospitalization 1. Bhatt DL et al. Am Heart J 2000; 140: Jarvis B, Simpson K. Drugs 2000; 60:

25 Interazione tra Clopidogrel e Inibitori di pompa protonica According to Laine and Hennekens November 13, 2009 Nuovi dati mostrano che quando clopidogrel e omeprazolo sono presi assieme l efficacia del clopidogrel è ridotta. Pazienti a rischio di infarto cardiaco o stroke in trattamento con clopidogrel non hanno pieno vantaggio dalla terapia se assumono anche Omeprazolo. entsandproviders/drugsafetyinformationforheathcareprofessionals/ucm htm

26 Interazione tra Clopidogrel e Inibitori di pompa protonica According to Laine and Hennekens November 13, 2009 Gli inibitori di pompa protonica sembrano diminuire ricorrenti sanguinamenti ulcerativi in corso di ASA così da poter continuare la terapia Raccomandazioni correnti non indicano specificamente clopidogrel in monoterapia ma stabiliscono che pazienti in duplice trattamento dovrebbero assumere PPI In caso di somministrazione contemporanea optare per Pantoprazolo e far trascorrere ore tra le somministrazioni Laine L and Hennekens CH. PPI and Clopidogrel Interaction: Fact or Fiction. AJG, Published online November 13, 2009.

27 ESPS 2: Effects on Stroke RRR (Pairwise Comparisons) 40.0% 37.0% P < % 30.0% 25.0% 20.0% 15.0% 16.3% P = % P = % P =.006 ASA/ER-DP vs Placebo ER-DP vs Placebo ASA vs Placebo 10.0% 5.0% ASA/ER-DP vs ASA 0.0% RRR ESPS 2 Group. J Neurol Sci. 1997;151(suppl):S1-S77.

28 ESPRIT Aspirin ( mg od) (n=1,376) vs Aspirin + dipyridamole (200 mg bd) (n=1,363) reclutati entro 6 mesi da un TIA/ictus aterotrombotico Trattamento aperto Follow-up medio di 3.5 years 1. ESPRIT study group et al. Lancet 2006;367:

29 ESPRIT Trial 3 gruppi di pazienti con TIA/stroke: ASA, ASA + DP, warfarin Outcome registrato in 1376 pz con ASA 1363 pz con ASA + DP 1 o evento in 173 (13%) dei ASA + DP 216 (16%) dei ASA hazard.80 (.66-98), ARR 1% per year ( ) Sanguinamenti essenzialmente uguali Dropout 34% ASA + DP, 14% ASA ESPRIT Study Group. Lancet. 2006;367:

30 Aspirin plus dipyridamole versus aspirin alone in cerebrovascular disease: ESPRIT Mean follow-up 3.5 years ,7 Events (%) ,7 Primary endpoint HR 0.80 (95% CI, ) 12,6 10,3 Major ischaemic events HR 0.81 (95% CI, ) Aspirin (n=1,376) Aspirin plus dipyridamole (n=1,363) CVD = TIA or minor ischaemic stroke of presumed arterial origin; primary endpoint = first occurrence of vascular death or non-fatal stroke, MI or major bleeding complication; major ischaemic events = non-haemorrhagic vascular death, non-fatal ischaemic stroke, non-fatal MI. ESPRIT, European/Australasian Stroke Prevention in Reversible Ischaemia Trial; HR, hazard ratio 1. ESPRIT study group et al. Lancet 2006;367:

31 PRoFESS: Primary Efficacy Outcome ER-DP + ASA Clopid o-grel Hazard Ratio (95% Confidence Interval) P Value First recurrent 9.0% 8.8% 1.01 ( stroke 1.11) Recurrent ischemic stroke 7.7% 7.9% Hemorrhagic stroke 0.8% 0.4% Sacco R. European Stroke Conference Webcast. Available at Accessed May 15, 2008.

32 MATCH: Primary End Point 0.20 IS, MI, VD, rehospitalization for acute ischemic event Placebo + Clopidogrel Cumulative event rate ASA + Clopidogrel RRR: 6.4% (P=.244) Months of follow-up Diener H-C. Antiplatelet therapy: results of the MATCH trial. Paper presented at: European Stroke Conference; May 13, 2004; Mannheim-Heidelberg, Germany.

33 MATCH: Emorragie rischio vita e maggiori 5 Bleeding Events (%) P < % Major Life-threatening 0 Placebo 0.6% + Clopidogrel 1.3% P <.0001 Aspirin + 2.5% Clopidogrel Nel MATCH c è una sovrarappresentazione ( > 50% ) di ictus da piccoli vasi ed il reclutamento era di ictus negli ultimi 6 mesi inoltre il follow-up era di lungo periodo. Diener HC, et al. Lancet. 2004;364;

34 CHARISMA: Study Design N=15,603 Symptomatic patients with Asymptomatic patients with coronary, cerebrovascular, or multiple atherothrombotic peripheral arterial disease* risk factors* n=12,153 (80%) n=3284 (20%) Clopidogrel 75 mg + ASA mg n=7802 Randomized, double-blind Placebo + ASA mg n=7801 Follow-up until 1040 primary events Primary end point: First occurrence of MI, stroke (any cause), CV death (including hemorrhagic) Principal secondary end point: First occurrence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization *n=166 not in either category, but included in overall analysis. Coronary, cerebral, or peripheral. CHARISMA=Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance. Bhatt DL et al. N Engl J Med. 2006;354:

35 CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death)* by Inclusion Criteria Population n RR (95% CI) P Value Documented CV disease 12, (0.77, 0.998).046 Coronary (0.71, 1.05).13 Cerebrovascular (0.65, 0.997).05 PAD (0.67, 1.13).29 Multiple risk factors (0.91, 1.59).20 Overall population 15, (0.83, 1.05) Clopidogrel better Placebo better *First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death. Bhatt DL. Presented at: American College of Cardiology Annual Scientific Session; March 11-14, 2006, Atlanta, GA. Bhatt DL, et al. N Engl J Med. 2006;354:

36 CHARISMA: Safety End Points by Inclusion Criteria Event Rate (%) Clopidogrel + ASA Placebo + ASA P Value Symptomatic Severe bleeding* Moderate bleeding* <.001 Asymptomatic Severe bleeding* Moderate bleeding* *Bleeding was defined using GUSTO criteria. GUSTO=Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. Bhatt DL et al. N Engl J Med. 2006;354:

37 CHARISMA: Tempi di Trattamento Stroke Clopidogrel + ASA Placebo + ASA RRR P <30 giorni 45/941 (4.78%) >30 giorni 60/1216 (4.93%) 65/967 (6.72%) 66/1196 (5.52%)

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39 Aumento del rischio per sottotipi 1. LAA compreso la stenosi intracranica associazione stretta con: i fattori di rischio (fumo,pad,pregresso stroke) deficit motorio ( afasia più correlata ai C.E.)

40 Stenosi carotidea 70% stenosi o superiore. Miglior terapia medica vs. TEA M edical Surgical Ipsilateral stroke 26.0% 9.0% M ajor or fatal ipsilateral stroke 13.1% 2.5% Stroke or death 32.3% 15.8% Solo se effettuata entro 14 giorni

41 Stenosi carotidea 50-69% stenosi Miglior terapia medica vs. TEA M e d ic a l S ur g ic a l Ip sila te r a l str ok e % % S tr ok e or d e a th % % Solo in alcuni sottogruppi: Evento recente Sintomi cerebrali non oculari Placca ulcerata Età avanzata Sesso maschile

42 ABCD 2 Score: 0 to 7 points Parameter Value Score Age 60 1 Blood pressure C Clinical features Duration of symptoms 140 sys. or 90 dias. unilateral weakness speech impairment without weakness other 60 min min < 10 min Diabetes yes 1 Lancet 2007;369:

43 CARESS 107 pazienti con TIA o stroke ischemico (da <3 mesi) dovuto a stenosi di Carotide interna e MES al TCD Clopidogrel 300 mg in acuto, poi 75 mg/d +ASA vs ASA Primary e-p proporzione di pazienti con MES in 7 giornata; frequenza di MES per ora in 2 e 7 giornata Significativa RRR nel gruppo Clopidogrel+ASA

44 CLAIR 100 pazienti con stenosi sintomatica arteriosa intra estracranica (TIA o Stroke da meno di 7 giorni e MES al TCD. Clopidogrel 300 mg in acuto, poi 75 mg/d +ASA vs ASA Primary e-p proporzione di pazienti con MES in 2^giornata Significativa RRR nel gruppo Clopidogrel+ASA

45 CURE: Patients with a Previous Stroke Event Rate (Myocardial Infarction, Stroke, or Cardiovascular Death) 25% 20% Placebo (+ASA) Clopidogrel (+ASA) 22.4% 45* 17.9% Events (%) 15% 10% 11.4% 21* 9.3% 11.0% 21* 8.9% 5% 0% All patients n=12,562 No previous stroke n=12,056 Previous stroke n=506 *Number of events prevented/1,000 patients treated On top of standard therapy (including ASA) 1) US Prescibing Information 2002 ; 2) Data on file, 2002, p87 internal CSR-EFC 3307.

46 Registro di un singolo Centro Clopidogrel + ASA dopo Stenting Carotideo (3) Conclusioni degli Autori: Terapia con doppia antiaggregazione piastrinica Clopidogrel + ASA in pazienti dopo stenting carotideo è associata ad una minor frequenza di eventi a 30 giorni. Source: D. Bhatt et al., J Invas Cardiol 2001: 13,

47 Terapia Antiaggregante piastrinica in caso di stroke non cardioemboolico Antiaggreganti migliori degli anticoagulanti (level A) Antiaggreganti accettabili ( level A) Aspirina (50-325mg/die) Aspirina più Dipiridamolo a lento rilascio Clopidogrel ( ASA inefficace o non tollerato) Aspirina più Dipiridamolo lento rilascio è indicata invece che ASA che rimane comunque la prima scelta ( level A) Aspirina più Clopidogrel non sono raccomandati per incremento del rischio emorragico ( level A)

48 TREATMENT ALGORITHM FOR SECONDARYPREVENTION OF STROKE (Lutsep H, Am J Med 2006)

49 Pazienti con condizioni specifiche di stroke: Dissecazione arteriosa In pazienti con stroke ischemico TIA e dissezione dei vasi sopraortici è indicato warfarin per 3-6 mesi o antiaggreganti piastrinici Dopo 3-6 mesi è ragionevole terapia antiaggregante piastrinica nella maggior parte degli stroke TIA. Terapia anticoagulante dopo i 6 mesi può essere considerata solo in pazienti con eventi ischemici ricorrenti. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

50 Pazienti con condizioni specifiche di Stroke Ipercoagulazione Pazienti con stroke TIA e trombofilia ereditaria stabilita dovrebbero essere valutati per trombosi venosa profonda che è una indicazione per la terapia anticoagulante di corto lungo periodo in relazione alle circostanze cliniche e ematologiche I pazienti dovrebbero essere valutati completamente per patogenesi alternativa in assenza di trombosi venosa, è indicata anticoagulazione a lungo termine o terapia antiaggregante. Pazienti con storia di eventi trombotici ricorrenti possono essere considerati per anticoagulazione a lungo termine Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

51 Stroke patients with Other Specific Conditions: Patent Foramen Ovale In pazienti con stroke TIA e PFO, è indicata la terapia antiaggregante. Warfarin è indicato in pazienti ad alto rischio che hanno altre indicazioni alla terapia anticoagulante come quelli con ipercoagulabilità di fondo o evidenza di trombosi venosa. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

52 pazienti con condizioni specifiche di stroke Sindrome da anticorpi antifosfolipidi In pazienti con stroke criptogenetico TIA e positività degli anticorpi antifosfolipidi è indicata terapia antiaggregante. Per pazienti con stroke TIA che soddisfano i criteri di sindrome da anticorpi APL con malattia occlusiva arteriosa e venosa in organi multipli, miscarriages e livedo reticularis è indicata terapia con anticoagulanti orali con target 2-3. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

53 Antiplatelet Therapy Which Recommendations Necessità di ulteriori evidenze: Leucoaraiosi e microsanguinamenti cerebrali asintomatici La Leucoaraiosi ed i microsanguinamenti cerebrali asintomatici sono associat con la emorragia cerebrale durante terapia anticoagulante o con aspirina. Così le alterazioni microvascolari viste all RMN non possono essere utilizzate per la gestione dei pazienti con fibrillazione atriale finchè non siano disponibili ulteriori dati su strategie ottimali per la gestione dei frmaci antitrombotici Atrial fibrillation and stroke prevention. Lancet Neurol 2007

54 Mosè riceve le compresse da Dio end

55 TIA non trattati diventano stroke: Dal 4 8% in 1 mese and 24 29% in 5 anni ( Heart Dis Stroke 1994) 10.5% in 90 giorni e la metà di essi avvengono nelle prime 48 ore ( JAMA 2002 ) TIA di prima insorgenza: ( Stroke 2003 ) 8.6 % divengono stroke nei primi 7 giorni 12% divengono stroke in 30 giorni

56 PRoFESS: Secondary Efficacy Outcome ER-DP + ASA Clopido- grel Hazard Ratio (95% Confidence Interval) P Value Stroke, MI, or vascular death 13.1% 13.1% 0.99 ( ) 0.83 Boehringer Ingelheim. Available at: Accessed May 14, 2008.

57 Treatment use over time: ESPRIT Aspirin alone: 13% discontinuation Mainly because of medical reasons, such as new TIA or stroke Aspirin + dipyridamole: 34% discontinuation Because of adverse effects mainly headaches) Patients on medication (%) Baseline 6 months Aspirin (n=1,376) Aspirin + dipyridamole (n=1,363) year years years years years years 1. ESPRIT study group et al. Lancet 2006;367:

58 Riduzione di Stroke fatali e non fatali 5 RRR = 22% P< % Incidence of Fatal and Nonfatal Stroke % * Results are for 66,860 patients who received antiplatelet treatment versus 67,021 who received control treatment 0 Antiplatelet Therapy Control (n=66,860) (n=67,021) RRR = relative risk reduction Adapted from Antiplatelet Trialists Collaboration. BMJ. 2002;324: Antithrombotic Trialists Collaboration. BMJ 2002; 324:

59 Effetti della terapia antiaggregante sullo stroke in pazienti ad alto rischio Category Acute MI suddivisi in varie categorie % Odds reduction Acute stroke Prior MI Prior stroke / TIA * Coronary artery disease, peripheral arterial disease, high risk of embolism and other high-risk conditions (including hemodialysis, diabetes mellitus, carotid disease) Other high risk* All trials 25% ± 3 (P<0.0001) Antiplatelet better Control better Adapted from Antiplatelet Trialists Collaboration. BMJ. 2002;324:

60 Effetti della terapia antiaggregante in pz ad Category alto rischio suddivisi per malattie Acute myocardial infarction Acute stroke Prior myocardial infarction Prior stroke / TIA Other high risk: Coronary artery disease (e.g., unstable angina, heart failure) Peripheral arterial disease (e.g. intermittent claudication) High risk of embolism (e.g. atrial fibrillation) Other (e.g. diabetes mellitus) % Odds reduction All trials 22% ±2 (P< ) * Vascular events = myocardial infarction, stroke or vascular death. Treatment effect Antiplatelet better Control better Adapted from Antiplatelet Trialists Collaboration. BMJ. 2002;324:

61 PRoFESS: Safety Major hemorrhagic events and intracranial bleeds occurred more frequently in the ER-DP plus ASA group compared with clopidogrel Major hemorrhagic events Intracranial hemorrhage* ER-DP + ASA Clopidogrel Hazard Ratio (95% Confidence Interval) 4.1% 3.6% 1.15 ( ) 1.4% 1.0% 1.42( ) P Valu e * All intracranial hemorrhages, which includes 128 of the 250 repeated ICH events, which were also reported in the primary outcome Sacco R. European Stroke Conference Webcast. Available at Accessed May 15, 2008.

62 Intracranial Stenosis WASID TRIAL: ASA vs warfarin in intracranial ICA, MCA, vertebral, basilar symptomatic stenoses No difference in combined death and stroke More deaths and bleeding in warfarin group Conclusion: ASA is the treatment of choice SAMMPRIS trial- stent vs ASA, underway

63 Fattori di rischio nei pazienti con CVD Pazienti con solo fattori di rischio multipli (%) Pazienti con CAD (%) Pazienti sintomatici Pazienti con CVD (%) Pazienti con AOP (%) Obesità (BMI 30 kg/m 2 ) Diabete trattato Ipertensione trattata Ipercolesterolemia trattata Fibrillazione atriale Tabagismo: corrente pregresso

64 aterosclerosi sintomatica nello studio CAPRIE (sovrapposizione tra AOP, Coronaropatia (CAD) (n=19.185) CAD e CVD) Malattia cerebrovascolare (CVD) 29,9% 7,3% 24,6% 3,3% 11,9% 3,8% 19,2% Arteriopatia obliterante periferica (AOP) CAPRIE Steeirng Committe Lancet 1996;348:

65 Incidenza di eventi CV dopo 1 anno di follow-up in funzione del numero dei Pazienti (%) vascolari coinvolti Numero distretti 26,3 0,8 vascolari coinvolti ,9 2,7 1,6 0,8 1,1 1,6 1,8 0,8 1,5 2,9 Morte CV IMA non fatale Ictus non fatale Morte CV/ Morte CV/IMA/ IMA/ictus ictus/ricovero 4,4 2,2 4,1 6,8 9,2 5,3 12,6 21,1 Steg G et al. JAMA 2007;297:

66 Incidenza di eventi CV dopo 1 anno di follow-up in base al tipo di patologia aterotrombotica 25 Pazienti (%) CAD CVD PAD Popolazione totale Solo FR multipli 21,1 15,2 14,5 12, ,9 2,1 2,5 1,7 0,8 PAD: Peripheral Arterial Disease Morte CV IMA non fatale Ictus non fatale Morte CV/ Morte CV/IMA/ IMA/ictus ictus/ricovero Steg G et al. JAMA 2007;297: ,7 1,4 1,3 1,4 1,9 1,7 1,0 1,1 0,8 0,8 4,5 6,5 5,4 4,2 2,2 5,3

67 Single Center Registry with Clopidogrel + ASA after Carotid Stenting (2) Procedural and 30-day event rates Clopidogrel (n = 139) Ticlopidine (n = 23) Procedural events Stroke Intracranial hemorrhage Myocardial Infarction Death Total 30 days (new events) Stroke Intracranial hemorrhage Myocardial Infarction Death Total Total (all events)* (PE) 3 (2.2%) (2.2%) 6 (4.3%) (8.7%) unclear 1 (4%) 3 (13%) *p = 0.03 Source: D. Bhatt et al., J Invas Cardiol 2001: 13, PE = pulmonary embolus; MI = Myocardial Infarction

68 AHA/ASA Recommendations Antiplatelet Therapy Noncardioembolic ischemic stroke/ TIA antiplatelet agents recommended, rather than oral anticoagulants (I,A) ASA, ASA/ER dipyridamole, and clopidogrel all acceptable for initial therapy (IIa, A) ASA/ER dipyridamole suggested over ASA alone (IIb, A) Clopidogrel may be considered over ASA alone (IIb, B) ASA + clopidogrel not routinely recommended for ischemic stroke/tia (III, A) Clopidogrel is reasonable for patients with ASA allergy (IIa, B). AHA/ASA Council on Stroke. Stroke. 2006;37:

69 Get With The Guidelines Stroke Performance on Selected Treatment and Quality of Care Indicators for Acute Stroke and Secondary Prevention (cont) Performance Indicator Baseline GWTG Antithrombotics at discharge* 91.0% 97.6% Anticoagulation for atrial fibrillation at discharge* 81.4% 97.6% Therapy at discharge if LDL >100 mg/dl or on therapy at 58.7% 81.6% admit* Counseling for smoking cessation* 38.8% 83.8% Lifestyle changes recommended for BMI >25 kg/m % 42.3% *Indicates 1 of the 7 key performance measures targeted in GWTG-Stroke. Data collected from 141,449 clinically identified patients admitted to 778 hospitals participating in the GWTG-Stroke program from January 1, 2006, through December 31, Fonarow GC. The first million patients in the Get With The Guidelines program: lessons learned. Accessed March 12, 2008.

70 Conclusions Ischemic stroke is a major cause of mortality and disability in the United States Most strokes could be prevented by risk factor Rx: diet, exercise, smoking cessation, BP, lipid Rx; important also for secondary prevention Carotid endarterectomy, stenting Anticoagulation for atrial fib, related disorders Antiplatelet therapy for all but warfarin-indicated patients; ASA, ASA-ER dipyridamole, clopidogrel New guidelines for secondary stroke prevention updated in 1/08

71 Death and recurrence at follow-up overall outcome at follow-up % Non compliance good bad At 3 months FU a significant correlation between percentage of NC and death or stroke recurrence has been detected (Wilcox test: p< ). At multivariate analysis percentage of NC, age and Rankin score at discharge emerged as independent predictors of outcome at 3 months.

72 Terapia antitrombotica prima dell evento Prma dell evento che ha determinato l inclusione nello studio il 61,5% dei pazienti affetti da ictus cerebrale ischemico era in terapia con aspirina Inefficacia? Scarsa compliance?

73 Eventi cardio e cerebrovascolari non fatali registrati nei 12 mesi di follow-up Tipo di evento Ictus ischemico Ictus emorragico Totale Infarto miocardico Intervento di rivascolarizzazione cardiaca TIA Recidiva Frequenza di ictus ictus recidivante 9% % Intervento di rivascolarizzazione cerebrale Edema polmonare Scompenso cardiaco Altro

74 Prescrizione di antitrombotici in rapporto alla dose 100 0,8% Dose raccomandata Dose superiore a quella raccomandata Dose inferiore a quella raccomandata 80 38,1% Percentuale ,2 92,2% % 85% 85,0% 60,9% Il 15% dei pazienti assume una dose insufficiente di ticlopidina. Il 38,1% dei pazienti assume una dose di ASA superiore a quella raccomandata. 0 15,0% Clopidogrel Ticlopidina ASA Antitrombotico 1%

75 Stroke patients with Other Specific Conditions: Arterial dissection For patients with ischemic stroke or TIA and arterial dissection, warfarin for 3 to 6 mo or antiplatelet agents are reasonable. Class IIa, Level B Beyond 3 to 6 mo, long-term antiplatelet therapy is reasonable for most ischemic stroke or TIA patients. Anticoagulant therapy beyond 3 to 6 mo may be considered among patients with recurrent ischemic events. Class IIb, Level C Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

76 Stroke patients with Other Specific Conditions: Hypercoagulable state Patients with an ischemic stroke or TIA with an established inherited thrombophilia should be evaluated for deep venous thrombosis, which is an indication for short- or long-term anticoagulant therapy, depending on the clinical and hematologic circumstances.class IIa, Level A Patients should be fully evaluated for alternative mechanisms of stroke. Class IIa, Level C. In the absence of venous thrombosis, long-term anticoagulation or antiplatelet therapy is reasonable. Patients with a history of recurrent thrombotic events may be considered for long-term anticoagulation. Class IIb, Level C Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

77 Stroke patients with Other Specific Conditions: Patent Foramen Ovale For patients with an ischemic stroke or TIA and PFO, antiplatelet therapy is reasonable to prevent a recurrent event. Warfarin is reasonable for high-risk patients who have other indications for oral anticoagulation such as those with an underlying hypercoagulable state or evidence of venous thrombosis. Class IIa, Level C Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

78 Stroke patients with Other Specific Conditions: Antiphospholipid Antibody Syndrome For cases of cryptogenic ischemic stroke or TIA and positive APL antibodies, antiplatelet therapy is reasonable For patients with ischemic stroke or TIA who meet the criteria for the APL antibody syndrome with venous and arterial occlusive disease in multiple organs, miscarriages, and livedo reticularis, oral anticoagulation with a target INR of 2 to 3 is reasonable. Class IIa, Level B Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

79 Antiplatelet Therapy Which Recommendations e) The needs of Further Evidences: LEUKOARAIOSIS AND ASYMPTOMATIC CEREBRAL MICROBLEEDS Leukoaraiosis and asymptomatic cerebral microbleeds are associated with intracranial haemorrhage during anticoagulation therapy and aspirin therapy. Hence, the microvascular changes seen on MRI cannot be applied to the management of patients with AF until further data are available on the optimal strategy for antithrombotic drug management. Atrial fibrillation and stroke prevention. Lancet Neurol 2007

80 Guideline for choice of therapy a) STROKE RISK AFTER TIA Age > 60 years (1 point) P.A. 140/90 (1 point) Focal weakness (2 points) Speech impairment without focal weakness (1 point) Duration 60 minutes (2 points) Duration minutes (1 point) Diabetes (1 point) RISK : High 6 7 Medium 4 5 Low 0-3 (Johnston, Rothwell et al.,lancet 2007)

81 COMORBIDITY Recent TIA and unstable angina or non-q wave myocardial infarction: Clopidogrel 75 mg and ASA mg EUSI 2004 Recent Coronay Acute Syndrome or Recent Coronary stent in previous nine months : Clopidogrel + ASA (Hankey et al. Neurology 2005) Carotid endarterectomy : ASA mg beginning before surgery AHA 1998 Peripheral arterial disease : Clopidogrel more effective than ASA (Aronow, 2007)

82 Selection of oral antiplatelet therapy Conclusions: Several factors may guide the decision to select a specific antiplatelet agent to initiate first afer TIA or ischemic stroke. Comorbid illnesses, side effects, and costs may influence the decision to initiate aspirin, combination aspirin and dipyridamole, or clopidogrel. At present, the selection of antiplatele therapy After stroke and TIA should be individualized. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack. Sacco et al, 2006

83 Summary: Aspirin in Primary Prevention of CVD In a comprehensive worldwide meta analysis of the 6 randomized trials of primary prevention aspirin produces a statistically significant and clinically important reduction in risk of a first myocardial infarction by about 1/3 but the available data on stroke and cardiovascular death remain inconclusive In these apparently healthy men and women at low risk aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. The average 10 year risk of a first CHD event among the apparently healthy men and women in the 6 randomized trials is less than 5%. The chief need is for randomized evidence in apparently healthy individuals whose 10 year risk of a first CHD event is 10-19%. 19%. Until then any decision to use aspirin in primary prevention should be an individual clinical judgement by the healthcare provider. Writing Group (Baigent C, Blackwell L, Buring J, Collins R, Emberson J, Godwin J, Hennekens C, Kearney P, Meade T, Patrono C, Peto R, Roncaglioni R, Zanchetti A). Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis analysis of individual participant data. Lancet. 2009;373:

84 10-Year Risk of a First CHD Event in the Six Major Trials of Aspirin in Primary Prevention of CVD WHS 2.5% HOT 3.6% PPP 4.3% PHS 4.8% BMD 8.9% TPT 12.4%

85 Dose Of Aspirin: Indirect Comparisons % Reduction Regimen No Trials (SE) 3P value Aspirin Alone (mg) (3) < (3) < (6) < < (8) NS Total (2) < X 32 het = 8.2, P=.04.. AntiThrombotic Trialists Collaboration. Lancet, 2002

86 Optimal Dosing For Aspirin In CHD Secondary Prevention & Primary Prevention 75 mg 325 mg Acute CVD Syndrome mg 325 mg Hennekens CH, Dyken M, Fuster V:Circ. 1997

87 Clopidogrel and PPI: Summary In several studies, omeprazole decreases pharmacodynamic effect of clopidogrel on surrogate markers such as platelet aggregation. Studies of the other individual PPIs have not shown such effects. Some, but not all, observational studies show that patients prescribed clopidogrel have small but significant effects of all 5 PPIs on increased rates of CV events in clopidogrel users. In one randomized trial designed to test the hypothesis, clopidogrel users randomized to omeprazole have no increased risk of CV events. Despite an insufficient totality of evidence, the FDA suggests that health care providers avoid prescribing omeprazole, esomeprazole, or cimetidine to patients receiving clopidogrel. When the totality of evidence is incomplete it is appropriate to remain uncertain. If a healthcare provider chooses to heed the FDA then use one of the other PPIs (e.g., pantoprazole, rabeprazole) and separate the PPI and clopidogrel by around hrs by prescribing the PPI before breakfast and clopidogrel at bedtime or PPI at dinner and clopidogrel at lunchtime

88 Warfarin Aspirin Recurrent Stroke Study (WARSS) 2200 ischemic, non A Fib stroke patients > 50% small vessel Warfarin INR v. ASA 325 mg No difference in stroke (trend favored ASA) Slight trend favoring warfarin in cryptogenic No difference: anticardiolipin Ab, PFO Warfarin: limited indications in stroke Mohr J, et al, for the WARSS Group. N Engl J Med. 2001;345:

89 Warfarin-Aspirin for Recurrent Probability of Event (%) Stroke Study (WARSS) Warfarin Aspirin Days after Randomization Number at Risk Warfarin Aspirin Mohr J, et al, for the WARSS Group. N Engl J Med. 2001;345:

90 Antiplatelet Therapies for Stroke Prevention Agent Mechanism Daily Dose Comment Aspirin Ticlopidine Cyclo-oxygenase inhibition ADP receptor blockade mg 25% stroke reduction 35% stroke reduction; 250 mg bid expensive, rash, diarrhea, leukopenia (1%) Clopidogrel ADP receptor blockade 75 mg 30% stroke reduction; non-toxic Dipyridamo le(with aspirin) Phosphodiesterase inhibition 200 mg bid (25 mg bid) 35-40% stroke reduction; headache in 6%

91 Antithrombotic Therapy for Stroke Prevention: Summary Situation Recommended Reasonable Options o 1 Cerebrovascular diseases - TIA or stroke ASA mg/d Clopidogrel; Ticlop. ASA + ER-DP - TIA or stroke on ASA Clopidogrel Ticlopidine ASA + ER-DP Warfarin INR Atrial Fibrillation -lone AF < 65 yr ASA 325 mg/d - -low risk yr ASA 325 mg/d Warfarin INR 2-3 -> 75 yr or high risk Warfarin INR 2-3 ASA if warfarin is contraindicated *ASA=aspirin; ER-DP=Extended release Dipyridamole

92 What about the patient who has a stroke while on ASA? Therapeutic Options: Maintain ASA (+/- increase dose) Switch to clopidogrel Add dipyridamole Switch to warfarin Add clopidogrel?

93 ACTIVE W Trial: Primary Efficacy Outcome: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death Cumulative Hazard Rates 0,10 0,08 0,06 0,04 0,02 RR = 1.45 p= Clopidogrel+ASA OAC 5.64 %/year 3.93 %/year Number at Risk 0,00 0,0 0,5 1,0 1,5 Years C+A 3,335 3,149 2, OAC 3,371 3,220 2, OAC oral anticoagulation Connolly S. et al. Lancet. 2006;367: Active W=The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events"

94 Single Center Registry with Clopidogrel Population: + ASA after Carotid Stenting (1) 162 patients with severe symptomatic (>70%) or asymptomatic (>80%) carotid artery stenosis who were not candidates for sugical endarterectomy Design: Prospective, single centre observational study all patients treated with: ASA 325mg + clopidogrel* (or ticlopidine in some cases) + heparin IV abciximab (bolus and infusion) in 82% of patients 4 weeks follow-up *most patients received loading dose of 300mg clopidogrel immediately after the procedure Source: D. Bhatt et al., J Invas Cardiol 2001: 13,

95 Time To Achieve Maximal Inhibition Of Serum Thromboxane B 2 With 75 mg ASA Hennekens CH and Schneider W. Expert Rev Cardiovasc Ther. 2008; 6: