Roberto Currò Dossi Stroke unit - Dipartimento di Medicina Interna

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1 Stroke ischemico/TIA: profilassi secondaria farmacologica “ideale” e reale
Roberto Currò Dossi Stroke unit - Dipartimento di Medicina Interna Azienda Sanitaria dell’Alto Adige Comprensorio Sanitario di Bolzano Trento 21 Novembre 2008

2 Prevenzione secondaria
Controllo dei fattori di rischio Ipertensione arteriosa Ipercolesterolemia Diabete mellito Terapia antitrombotica Antiaggreganti Anticoagulanti Guidelines Ischaemic Stroke 2008

3 Ipertensione arteriosa
Basi scientifiche Una meta-analisi di sette trials randomizzati ha mostrato che i farmaci anti-ipertensivi riducono il rischio di recidiva di stroke dopo stroke e TIA (RR 0.76; 95% CI )1 Il target pressorio assoluto e l'entità della riduzione pressoria non sono definiti e dovrebbero essere individualizzati La riduzione del rischio di stroke avviene indipendentemente dal valore pressorio di partenza e dal tipo di stroke2 A meta-analysis of seven randomized controlled trials showed that antihypertensive drugs reduced stroke recurrence after stroke or TIA (RR 0.76; 95%CI ) {Rashid, 2003 #897}. This analysis included the PATS (indapamide, a diuretic), HOPE (ramipril) and PROGRESS (perindopril, with or without indapamide) studies {Group, 1995 #828;Yusuf, 2000 #201;Bosch, 2002 #827;PROGRESS collaborative group, 2001 #141}. The reduction in stroke occurs regardless of BP and type of stroke {PROGRESS collaborative group, 2001 #141}. BP should be lowered and monitored indefinitely after stroke or TIA. The absolute target BP level and reduction are uncertain and should be individualized, but benefit has been associated with an average reduction of about 10/5 mm Hg, and normal BP levels have been defined as <120/80 mm Hg {Chobanian, 2003 #883}. However, blood pressure should not be lowered intensively in patients with suspected haemodynamic stroke. The angiotensin receptor antagonist eprosartan may be more effective than the calcium channel blocker nitrendipine 1: Rashid P et al.: Stroke (2003) 34:2741-8 2: PROGRESS group: Lancet (2001) 358: Guidelines Ischaemic Stroke 2008

4 Controllo dei fattori di rischio
Raccomandazioni E’ indicato un controllo regolare della pressione arteriosa. Dopo la fase acuta dello stroke l'abbassamento della pressione arteriosa è indicato anche nei pazienti normotesi (Classe I, Livello A) Guidelines Ischaemic Stroke 2008

5 Raccomandazione 12.6 Grado B
Nei pazienti con pregresso ictus o TIA è indicato il miglior controllo possibile dell’ipertensione arteriosa usando preferibilmente farmaci che agiscono sul sistema renina-angiotensina, calcio antagonisti e diuretici. Nei pazienti con ictus o TIA è indicato l’uso dell’ACE-inibitore perindopril, associato al diuretico indapamide, o il sartanico eprosartan, per ottenere un’adeguata riduzione pressoria e la prevenzione di nuovi eventi cerebrovascolari. 5

6 Ipercolesterolemia Basi scientifiche
L’atorvastatina (80mg) reduce il rischio di recidiva di stroke del 16%1 La simvastatina (40mg) riduce il rischio di eventi vascolari in pz con pregresso stroke e il rischio di stroke in pz. con altra patologia vascolare (RR 0.76)2 L’ ARR per la terapia con statine è basso (NNT for 1 year)1 In the SPARCL trial, statin therapy with atorvastatin reduced stroke recurrence (HR 0.84; 95%CI ) {Amarenco, 2006 #824}, while in the Heart Protection Study simvastatin reduced vascular events in patients with prior stroke, and reduced stroke in patients with other vascular disease (RR 0.76) {Heart Protection Study Collaborative Group, 2002 #96}. Neither trial assessed efficacy by stroke subtype, and SPARCL did not include patients with presumed cardioembolic stroke {Heart Protection Study Collaborative Group, 2002 #96;Amarenco, 2006 #824}. The risk of haemorrhagic stroke was slightly increased in both trials {Heart Protection Study Collaborative Group, 2002 #96;Amarenco, 2006 #824}. The absolute risk reduction achieved with statin therapy is low (NNT for 1 year). Statin withdrawal at the acute stage of stroke may be associated with an increased risk of death or dependency {Blanco, 2007 #932}. HPS Findings Overall, there was a highly significant 25% (95% CI 15–34) proportional reduction in the first event rate for stroke (444 [4·3%] simvastatin vs 585 [5·7%] placebo; p<0·0001), reflecting a definite 28% (19–37) reduction in presumed ischaemic strokes (p<0·0001) and no apparent difference in strokes attributed to haemorrhage (51 [0·5%] vs 53 [0·5%]; rate ratio 0·95 [0·65–1·40]; p=0·8). In addition, simvastatin reduced the numbers having transient cerebral ischaemic attacks alone (2·0% vs 2·4%; p=0·02) or requiring carotid endarterectomy or angioplasty (0·4% vs 0·8%;p=0·0003). The reduction in stroke was not significant during the first year, but was already significant (p=0·0004) by the end of the second year. Among patients with pre-existing cerebrovascular disease there was no apparent reduction in the stroke rate, but there was a highly significant 20% (8–29) reduction in the rate of any major vascular event (406 [24·7%] vs 488 [29·8%]; p=0·001). The proportional reductions in stroke were about one-quarter in each of the other subcategories of participant studied, including: those with coronary disease or diabetes; those aged under or over 70 years at entry; and those presenting with different levels of blood pressure or lipids (even when the pretreatment LDL cholesterol was below 3·0 mmol/L [116 mg/dL]). Interpretation Much larger numbers of people in the present study suffered a stroke than in any previous cholesterol lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischaemic strokes, with no apparent effect on cerebral haemorrhage, even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischaemic strokes by about one-quarter and so, after making allowance for noncompliance in the trial, actual use of this regimen would probably reduce the stroke rate by about a third. HPS also provides definitive evidence that statin therapy is beneficial for people with pre-existing cerebrovascular disease, even if they do not already have manifest coronary disease. Lancet 2004; 363: 757–67 SPARCL 2006 Results The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P = 0.03; unadjusted P = 0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of majorcardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P = 0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P = 0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. Conclusions In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. N Engl J Med 2006;355: SPARCL 2007 Results—Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with 50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P0.0016), a 33% reduction in ischemic stroke (P0.0018), no statistically significant increase in hemorrhagic stroke (P0.8864), and a 37% reduction in major coronary events (P0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with 50% LDL-C reduction. Conclusions—As compared with having no change or an increase in LDL-C, achieving a 50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages. Stroke. 2007;38: 1: Amarenco P et al.: N Engl J Med (2006) 355: 2: Heart Protection Study: Lancet (2002) 360:7-22 Guidelines Ischaemic Stroke 2008

7 Controllo dei fattori di rischio
Raccomandazioni La terapia con statine è indicata in pazienti con ictus non cardioembolico (Classe I, Livello A) Guidelines Ischaemic Stroke 2008

8 Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack Nuova raccomandazione In base allo studio SPARCL, la somministrazione di statine con effetto ipolipemizzante intensivo è raccomandata nei pazienti con stroke ischemico o TIA aterosclerotici e senza nota coronaropatia, per ridurre il rischio di stroke e di eventi cardiovascolari (Classe I, Livello B ) Stroke. 2008;39:

9 Terapia antitrombotica
Basi scientifiche: ASA RRR 13% di stroke dopo stroke o TIA1 I dosaggi più studiati sono quelli tra 50 e 150 mg L’incidenza di effetti collaterali gastrici è dose-dipendente Non è stata rilevata una differenza di efficacia tra il dosaggio basso (< 160mg), medio (160 – 325mg) o alto ( mg) Antiplatelet therapy reduces vascular events, including non-fatal myocardial infarction, nonfatal stroke and vascular death in patients with previous stroke or TIA (RR 0.78; 95%CI ) {Antithrombotic Trialists' Collaboration, 2002 #9}. Aspirin Aspirin reduces recurrence independent of dose (50 to 1300 mg/d) {Algra, 1996 #7;The Dutch TIA Trial Study Group, 1991 #171;Farrell, 1991 #68;Campbell, 2007 #808}, although high doses (>150mg/day) increase adverse events. In patients with symptomatic intracranial atherosclerosis, aspirin is as effective as oral anticoagulation and has fewer complications {Chimowitz, 2005 #807}. 1: Antithrombotic Trialists' Collaboration: BMJ (2002) 324:71-86 Guidelines Ischaemic Stroke 2008

10 Terapia antitrombotica
Basi scientifiche: clopidogrel Clopidogrel è lievemente ma significativamente più efficace dell’ASA a dosaggio intermedio (RRR 8.7%, ARR 0,5%) nel prevenire gli eventi vascolari in pazienti con pregresso stroke, IMA o arteriopatia periferica1 : Clopidogrel is slightly more effective than aspirin in preventing vascular events (RR 0.91; 95%CI ) {CAPRIE Steering Committee, 1996 #35}. It may be more effective in high-risk patients (i.e. those with previous stroke, peripheral artery disease, symptomatic coronary disease, or diabetes) {Bhatt, 2006 #836}. 1: CAPRIE Steering Committee: Lancet (1996) 348: Guidelines Ischaemic Stroke 2008

11 Terapia antitrombotica
Basi scientifiche: dipiridamolo + ASA RRR di morte vascolare, stroke o IMA significativamente maggiore rispetto ad ASA (RR 0.82; 95%CI )1,2. ARR 1.0% per anno (NNT 100)2 Dipyridamole alone reduces stroke recurrence with similar efficacy to aspirin {Diener, 1996 #54}. The combination of aspirin ( mg/d) and dipyridamole (200 mg extended release twice daily) reduces the risk of vascular death, stroke or MI, compared with aspirin alone (RR 0.82; 95%CI ) {Diener, 1996 #54;Halkes, 2006 #810}. Dipyridamole may cause headache; the incidence of this may be reduced by increasing the dose gradually {Chang, 2006 #933;Diener, 2007 #945}. 1: Diener HC et al.: J Neurol Sci (1996) 143:1-13 2: Halkes P et al.: Lancet (2006) 367: Guidelines Ischaemic Stroke 2008

12 Aspirin and extended-release dipyridamole vs clopidogrel for recurrent stroke
Figure 1. Kaplan–Meier Estimates of the Cumulative Probability of Primary and Secondary Outcomes, According to Treatment Group. The primary outcome of first recurrence of stroke (Panel A) occurred in 916 of 10,181 patients (9.0%) treated with aspirin plus extended-release dipyridamole (ERDP) and in 898 of 10,151 patients (8.8%) treated with clopidogrel (hazard ratio for aspirin–ERDP, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The main secondary outcome of stroke, myocardial infarction (MI), or death from vascular causes (Panel B) occurred in 1333 patients (13.1%) in each of the two groups (hazard ratio for aspirin–ERDP, 0.99; 95% CI, 0.92 to 1.07). The estimated hazard ratios are based on a Cox model with covariates of baseline values of age, use or nonuse of angiotensin-converting–enzyme inhibitors, diabetes status, and score on the modified Rankin scale. Results A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA–ERDP recipients [11.7%], vs clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). Conclusions The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA–ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. N Engl J Med 2008;359: PRoFESS N Engl J Med 2008;359:

13 Terapia antitrombotica
Raccomandazioni E’ indicato che i pazienti con pregresso stroke ischemico o TIA vengano trattati con terapia antitrombotica (Class I, Level A) E’ indicato che i pazienti che non necessitano di anticoagulanti vengano trattati con antiaggreganti (Classe I, Livello A). Ove possibile, dovrebbero essere somministrati ASA + dipiridamolo o clopidogrel da solo. Alternativamente possono essere utilizzati ASA o triflusal da soli (Classe I, Livello A) Guidelines Ischaemic Stroke 2008

14 Terapia antitrombotica
Basi scientifiche: clopidogrel + ASA Paragonata a clopidogrel da solo, la combinazione di clopidogrel + ASA non riduce il rischio di stroke ischemico, IMA, morte vascolare o di nuova ospedalizzazione1 Paragonata ad ASA da sola, la combinazione di clopidogrel + ASA non riduce il rischio di IMA, stroke o morte cardiovascolare2 La combinazione clopidogrel + ASA aumenta il rischio di emorragie maggiori o a rischio per la vita1,2 Compared with clopidogrel alone, the combination of aspirin and clopidogrel did not reduce the risk of ischaemic stroke, myocardial infarction, vascular death, or re-hospitalisation {Diener, 2004 #809}; however, life-threatening or major bleeding were increased with the combination. Similarly, in the CHARISMA study, the combination of aspirin and clopidogrel did not reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes, compared with aspirin alone {Bhatt, 2006 #836}. In patients who have had an acute coronary event within 12 months, or coronary stenting, the combination of clopidogrel and aspirin reduces the risk of new vascular events {Yusuf, 2001 #902}. 1: Diener H et al.: Lancet (2004) 364: 2: Bhatt D et al.: N Engl J Med (2006) 354: Guidelines Ischaemic Stroke 2008

15 Fixed-effects meta-analysis of 90-day risk of combined outcome of stroke, transient ischaemic attack, acute coronary syndrome, and all-cause death in patients enrolled within 24 h of onset of stroke or transient ischaemic attack absolute stroke risk reduction = 3·8% Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial James Kennedy, Michael D Hill, Karla J Ryckborst, Michael Eliasziw, Andrew M Demchuk, Alastair M Buchan, for the FASTER Investigators* Findings The median time to stroke outcome was 1 day (range 0–62 days). The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins. 14 (7·1%) patients on clopidogrel had a stroke within 90 days compared with 21 (10·8%) patients on placebo (risk ratio 0·7 [95% CI 0·3–1·2]; absolute risk reduction −3·8% [95% CI −9·4 to 1·9]; p=0·19). 21 (10·6%) patients on simvastatin had a stroke within 90 days compared with 14 (7·3%) patients on placebo (risk ratio 1·3 [0·7–2·4]; absolute risk increase 3·3% [−2·3 to 8·9]; p=0·25). The interaction between clopidogrel and simvastatin was not significant (p=0·64). Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo (absolute risk increase 1·0% [−0·4 to 2·4]; p=0·5). There was no difference between groups for the simvastatin safety outcomes. Interpretation Immediately after TIA or minor stroke, patients are at high risk of stroke, which might be reduced by using clopidogrel in addition to aspirin. The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit. We were unable to provide evidence of benefit of simvastatin in this setting. This aggressive prevention approach merits further study. 12. compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–37. 22. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–17. 23. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005; 111: 2233–40. Lancet Neurol 2007; 6: 961–69

16 Terapia antitrombotica
Raccomandazioni La combinazione di ASA + clopidogrel non è indicata in pazienti con stroke ischemico recente, eccetto nei pazienti con specifiche indicazioni (p.e. angina instabile o IMA non-Q, stenting recente); tale trattamento dovrebbe essere continuato fino a un massimo di 9 mesi dall’evento (Classe I, Livello A) Guidelines Ischaemic Stroke 2008

17 Terapia antitrombotica
Raccomandazioni E’ indicato che i pazienti con recidiva di stroke ischemico durante terapia anti-aggregante debbano essere rivalutati riguardo alla fisiopatologia ed ai fattori di rischio (Classe IV, GCP) Guidelines Ischaemic Stroke 2008

18 Anticoagulazione Basi scientifiche:
La TAO (INR target 2.0 – 3.0) riduce il rischio di recidiva di stroke ischemico in pazienti con FA non valvolare (cronica o parossistica)1 La TAO è una profilassi ben stabilita per altre cause di cardioembolia come le protesi valvolari meccaniche, la valvulopatia reumatica, l’aneurisma ventricolare e la cardiomiopatia dilatativa Non c’è indicazione alla TAO nello stroke ischemico non cardioembolico2 Oral anticoagulation after non-cardiac ischaemic strokes is not superior to aspirin, but causes more bleeding {Mohr, 2001 #128;The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group, 1997 #177;Algra, 2007 #903}, Oral anticoagulation (INR 2.0–3.0) reduces the risk of recurrent stroke in patients with non-valvular AF (whether of permanent, chronic or paroxysmal type) {EAFT (European Atrial Fibrillation Trial) Study Group, 1993 #835} and most other cardiac sources of emboli. Anticoagulation should be taken long term, or for at least 3 months after MI {Visser, 1984 #954}. 1: EAFT Study Group: Lancet (1993) 342: 2: Mohr JP et al.: N Engl J Med (2001) 345: Guidelines Ischaemic Stroke 2008

19 Anticoagulazione Situazioni particolari
In pazienti con FA e coronaropatia stabile l’ASA non dovrebbe essere aggiunta alla TAO1 Alcuni studi retrospettivi suggeriscono che l’anticoagulazione può essere efficace nell’ateroma aortico2, negli aneurismi fusiformi dell’arteria basilare3 o nelle dissezioni dei vasi epiaortici4 Non è chiaro se i pazienti con PFO traggano beneficio dalla TAO5 In patients with AF and stable coronary disease, aspirin should not be added to oral anticoagulation {Flaker, 2006 #955}. Anticoagulation may be beneficial in patients with aortic atheroma {Dressler, 1998 #58}, fusiform aneurysms of the basilar artery {Echiverri, 1989 #61} or cervical dissection {Engelter, 2007 #935}. It is unclear if patients with patent foramen ovale benefit from oral anticoagulation. Patients without proven deep vein thrombosis (DVT) or atrial septal aneurysm should be given aspirin. The roles of anticoagulation and closure of the patent foramen ovale in patients with proven DVT or atrial septal aneurysm remain to be elucidated {Mas, 2001 #124}. 1: Flaker GC et al.: Am Heart J (2006) 152:967-73 2: Dressler FA et al.: J Am Coll Cardiol (1998) 31:134-8 3: Echiverri HC et al.: Stroke (1989) 20:1741-7 4: Engelter ST et al.: Stroke (2007) 38: 5: Mas JL et al.: N Engl J Med (2001) 345:1740-6 Guidelines Ischaemic Stroke 2008

20 Terapia antitrombotica
Raccomandazioni La TAO (INR 2.0–3.0) è indicata dopo stroke ischemico associato a FA (Classe I, Livello A) La TAO (INR ) è indicata dopo stroke ischemico cardioembolico non correlato a FA se il rischio di recidiva è alto (Classe III, Livello C) Guidelines Ischaemic Stroke 2008

21 Terapia antitrombotica
Raccomandazioni La TAO non dovrebbe essere utilizzata dopo stroke ischemico non cardioembolico eccetto in alcune situazioni specifiche come l’ateroma aortico, l’aneurisma fusiforme dell’arteria basilare, le dissezioni dei vasi epiaortici o un PFO associato a TVP o aneurisma del setto interatriale (Class IV, GCP) Guidelines Ischaemic Stroke 2008

22 Raccomandazione 12.14 Grado C
In pazienti portatori di protesi valvolari meccaniche con recidiva di ictus dopo ictus ischemico o TIA, durante un trattamento con anticoagulanti orali a dose appropriata, è indicata l’associazione di anticoagulanti orali e dipiridamolo 400 mg/die o ASA 100 mg/die. 22

23 Terapia antitrombotica
Raccomandazioni L’età avanzata di per sé non è una controindicazione alla TAO (Classe I, Livello A) La TAO non è raccomandata in pazienti con comorbidità come tendenza alle cadute, scarsa compliance, epilessia non controllata o emorragie gastro-intestinali (Classe III, Livello C). In caso di controindicazioni alla TAO è indicato il trattamento con ASA + dipiridamolo (Class IV, GCP) Guidelines Ischaemic Stroke 2008

24 Studio SIRIO (2005) N. pazienti 3.018 M 1.710 (56.7%) F 1.308 (43.3%)
Età media aa 72.2±12.2 Stroke ischemico 2.573 (85.3%) Stroke emorragico 445 (14.7%) SIRIO: Stroke in Italy and Related Impact on Outcome Studio multicentrico osservazionale promosso da Italian Stroke Forum Ogni centro partecipante ha registrato per quattro mesi tutti i casi d i ictus ischemico o emorragico, con l’esclusione delle emorragie subaracnoidee, verificatisi tra il primo gennaio e il 31 ottobre 2005 Considerando che il numero di soggetti presumibilmente arruolabili per centro si attesta intorno a 30~35 nel periodo di arruolamento previsto, verranno selezionati per lo studio circa 135 centri. Ciascun centro contribuirà allo studio con tutti i soggetti eleggibili che si presentino nel corso del periodo previsto per l’arruolamento (4 mesi consecutivi). 24

25 Registro REACH ( ) pazienti in centri* in 44 paesi. 17.923 5.657 27.786 5.916 Giappone 5.197 847 Nord America America Latina The Reduction of Atherothrombosis for Continued Health (REACH) Registry collected data on atherosclerosis risk factors and treatment. A total of 67 888 patients aged 45 years or older from 5473 physician practices in 44 countries had either established arterial disease (coronary artery disease [CAD], n = 40 258; cerebrovascular disease, n = 18 843; peripheral arterial disease, n = 8273) or 3 or more risk factors for atherothrombosis (n = 12 389) between 2003 and 2004 1.931 Europa occidentale Europa orientale 2.872 Medio Oriente Asia Australia *fino a 15 pazienti/centro (fino a 20 negli USA)

26 Terapia antitrombotica pre-evento
Not treated Treated 100 83,9 80 62,8 60 % 37,2 40 Solo il 63% dei pazienti che aveva necessità di un trattamento antitrombotico di fatto lo effettuava mentre il 16% effettuava tale trattamento senza averne una obiettiva necessità. I pazienti inclusi nello studio sirio per un ictus ischemico sono 2761, con una maggior prevalenza (57%) di maschi. Il 25% di questi pazienti aveva già presentato un pregresso TIA o ictus cerebrale. 16,1 20 Not needing Needing antithrombotics antithrombotics

27 Trattamento dei pazienti con aterotrombosi dei grossi vasi
100 Maschi Femmine 80 60 % 40 20 Antiaggreganti Anticoagulanti Eparina Niente

28 Trattamento dei pazienti con stroke lacunare
100 Maschi Femmine 80 60 % 40 20 Antiaggreganti Anticoagulanti Eparina Niente

29 Trattamento dei pazienti con fibrillazione atriale
60 Maschi Femmine 50 40 % 30 20 10 Antiaggreganti Anticoagulanti Eparina Niente

30 Prescrizione di antitrombotici Adeguatezza del dosaggio
… 0.8% 100 80 38.1% dose level 60 below recommended 85.0% recommended % 99.2% above recommended 40 Il dosaggio è risultato adeguato per la prescrizione di clopidogrel, non adeguato nel 15% dei casi ai quali era prescritta la ticlopidina, eccessivo nel 38% dei pazienti trattati con aspirina. 60.9% 20 15.0% 1.0% … clopidogrel ticlopidine ASA antithrombotic

31 Colesterolemia ≥200 mg/dL
Undertreatment dei fattori di rischio vascolari nei pazienti ambulatoriali con aterotrombosi 100 80 Nord America 65 64 60 America Latina 60 56 56 Europa occidentale 53 52 48 Europa orientale Pazienti% 44 43 43 43 Medio Oriente 40 40 34 Asia Australia 28 24 Giappone 20 The REduction of Atherothrombosis for Continued Health (REACH) Registry International Prevalence, Recognition, and Treatment of Cardiovascular Risk Factors in Outpatients With Atherothrombosis PA ≥140/90 mmHg Colesterolemia ≥200 mg/dL Bhatt DL et al. JAMA 2006;295:

32 Sottoutilizzo delle terapie stabilite nei pazienti ambulatoriali con aterotrombosi
pazienti non trattati 60 Antiaggreganti 50 46 44 Statine 40 36 Pazienti% 28 30 24 18 18 20 14 International Prevalence, Recognitionand Treatment of Cardiovascular Risk Factors in Outpatients With Atherothrombosis 10 CAD (n=40.258) CVD (n=18.843) AOP (n=8.273) Fattori di rischio multipli (n=12.389) Bhatt DL et al. JAMA 2006;295:

33 I pazienti con PAD e CVD hanno meno possibilità dei pazienti con CAD di utilizzare le terapie stabilite pazienti trattati Pazienti con sola CAD 97,4 100 94,1 92,4 Pazienti con sola CVD 85,6 85,6 81,8 81,7 82,5 82,2 80,9 Pazienti con sola PAD 80 70,0 61,3 Pazienti% 60 40 20 Anti-ipertensivi Antiaggreganti Antidiabetici orali Ipolipemizzanti Bhatt DL et al. JAMA 2006;295:

34 Hypertension treatment and control in five European Countries, Canada, and the USA
80 USA Canada 70 Italia Svezia 60 Spagna Inghilterra 50 Germania Popolazione (%) 40 TABLE 4. Age-Adjusted Hypertension Awareness, Treatment, and Control in the Population and Control in Treated Hypertensive Patients Aged 35–64 Years at the 140/90 mm Hg Threshold Hypertension is poorly controlled, even in western industrialized societies, as revealed in a survey of studies on hypertension treatment and control.1 Many patients, especially in Europe, are not even aware that they have hypertension. Many patients are not treated even when they have been diagnosed. Fewer than 30% of patients have their blood pressure reduced to recommended levels (i.e. <140/90 mmHg). Wolf-Maier K et al. Hypertension Treatment and Control in Five European Countries, Canada, and the United States. Hypertension 2004;43:10–17. 30 20 10 consapevolezza terapia controllo * Livello soglia sist/diast = 140/90 mm Hg Wolf-Maier et al. Hypertension 2004;43:10–17

35 Antithrombotic drug prescription per risk category according to the
CHADS2 score Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation The CHADS2 (Congestive heart failure, Hypertension, Age .75 years,Diabetes mellitus, and Stroke/TIA) stroke risk score is based on stroke risk classification schemes of the Stroke Prevention in Atrial Fibrillation (SPAF) trial investigators and the AF Investigators (AFI) and was validated in the National Registry of AF cohort on patients not receiving OAC.6 The CHADS2 scheme produces a score from 0 to 6 for patients with non-valvular AF. …..the CHADS2 score was superior in identifying patients at high risk (>=2). Those defined as ‘high risk’ …..had just a slightly higher chance of receiving OAC or any antithrombotic therapy in general, which was also previously shown for the ACC/AHA/ESC guidelines.23 Therefore, regardless of the choice for any scheme, antithrombotic therapy prescription seems to be marginally guided by current available stroke risk stratification schemes. Important factors in the decision-making process regarding antithrombotic treatment First detected or paroxysmal AF had a lower chance of receiving OAC compared with patients with persistent or permanent AF, which was in accordance with previous findings.23 This might relate to the fact that a low AF burden is thought to be associated with a low risk for stroke. ...to date there is very limited evidence that a high AF burden is associated with an increased risk for stroke24, OAC has been shown to be effective in both paroxysmal (intermittent) and persistent AF patients, although evidence to support this is also quite limited and addressed patients with long-lasting intermittent episodes of AF rather than paroxysmal AF according to the current definition of the guidelines.26 An important factor complicating this issue is that the physicians' perception of AF burden mostly underestimates the true AF burden, as many patients suffer from asymptomatic recurrences.27 At the present time, the main focus in this decision-making process should therefore be on the presence of high risk factors for stroke, rather than on the clinical type of AF per se. AF as only reason for the qualifying admission or visit, OAC was prescribed more often. This could be due to less distraction by other medical problems or management by an AF specialized physician who is more aware of the importance of OAC. Availability of an OAC monitoring outpatient clinic also played a significant role in the decision-making process. A (prior) major bleeding was a factor against prescribing any antithrombotic drugs. However, we did not know in detail what kind of bleeding was present, nor how long ago it was diagnosed. Remarkable was the finding that a surprising 40–50% of low-risk patients received OAC. These patients are exposed to an avoidable bleeding hazard, as a platelet inhibitor would suffice in these patients. Valvular heart disease played a significant role in the prescription of OAC and to a lesser extent also diabetes. Surprisingly, a (prior) stroke or TIA, but also hypertension and age >75 years were not significantly associated with OAC prescription, and even more remarkable was that heart failure did not play a role in any of the multivariable analyses. Combination of OAC and antiplatelet drugs A combination of OAC and an antiplatelet agent is given in 8% of patients. Little evidence exists for the additive benefit of aspirin to OAC as thromboprophylaxis in AF per se, but it increases the risk of bleeding.29 Physicians still consider this combination as beneficial in vascular disease, but in reality the benefits express mainly in the first 35 days after an acute coronary event, rather than in the long-term.30 The lower application of combination therapy in the presence of an OAC monitoring clinic might reflect more frequent and strict monitoring of evidence-based antithrombotic drug prescription and confidence that stand alone OAC is adequate even in very high-risk patients. Congestive heart failure Hypertension Age >75 years Diabetes mellitus Stroke/TIA Nieuwlaat, R. et al. Eur Heart J :

36 Risk for arterial thromboembolism in patients receiving aspirin + oral anticoagulant (OAC) therapy or OAC therapy alone Data Synthesis: Ten studies were included, totaling 4180 patients. The risk for arterial thromboembolism was lower in patients receiving combined aspirin-OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, ). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, ). There was no difference in the risk for arterial thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, ) or coronary artery disease (OR, 0.69; 95% CI, ). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, ). The risk for major bleeding was higher in patients receiving aspirin-OAC therapy compared with OAC therapy alone (OR,1.43; 95% CI, ). Conclusion: Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding. Dentali, F. et al. Arch Intern Med 2007;167: Dentali, F. et al. Arch Intern Med 2007;167:

37 Risk for major bleeding in patients receiving aspirin + oral anticoagulant (OAC) therapy or OAC therapy alone Data Synthesis: Ten studies were included, totaling 4180 patients. The risk for arterial thromboembolism was lower in patients receiving combined aspirin-OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, ). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, ). There was no difference in the risk for arterial thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, ) or coronary artery disease (OR, 0.69; 95% CI, ). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, ). The risk for major bleeding was higher in patients receiving aspirin-OAC therapy compared with OAC therapy alone (OR,1.43; 95% CI, ). Conclusion: Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding. Dentali, F. et al. Arch Intern Med 2007;167: Dentali, F. et al. Arch Intern Med 2007;167:

38 Risk for all-cause mortality in patients receiving aspirin + oral anticoagulant (OAC) therapy or OAC therapy alone Data Synthesis: Ten studies were included, totaling 4180 patients. The risk for arterial thromboembolism was lower in patients receiving combined aspirin-OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, ). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, ). There was no difference in the risk for arterial thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, ) or coronary artery disease (OR, 0.69; 95% CI, ). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, ). The risk for major bleeding was higher in patients receiving aspirin-OAC therapy compared with OAC therapy alone (OR,1.43; 95% CI, ). Conclusion: Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding. Dentali, F. et al. Arch Intern Med 2007;167: Dentali, F. et al. Arch Intern Med 2007;167:

39 Missed opportunities for secondary prevention of cerebrovascular disease in elderly british men from 1999 to 2005: a population-based study Cosa è già noto L’efficacia dei farmaci antiaggreganti, anti-ipertensivi (soprattutto in combinazione) e ipocolesterolemizzanti nel ridurre il rischio di eventi vascolari in pazienti con malattia cerebrovascolare è attualmente stabilita anche nei pazienti geriatrici L’uso di questi farmaci nel prevenire le recidive di stroke è stato inoltre dimostrato essere economicamente vantaggioso Dato l’aumentato rischio di stroke nei pazienti geriatrici, la necessità di una prevenzione secondaria è ancora maggiore J Public Health.  2007;29(3):

40 Risultati dello studio
Missed opportunities for secondary prevention of cerebrovascular disease in elderly british men from 1999 to 2005: a population-based study Risultati dello studio Età avanzata, diagnosi di TIA piuttosto che di stroke e assenza di coesistente coronaropatia sono associate a un minor uso di specifiche classi di farmaci, soprattutto di statine Il sottoutilizzo della profilassi secondaria farmacologica sembra in gran parte riflettere un’insufficiente prescrizione e non un’insufficiente compliance da parte dei pazienti cerebrovascolari J Public Health.  2007;29(3):