Prevenzione e Trattamento della Malattia Cardiovascolare

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1 Pavia Spring Meeting on Thrombosis Giugno 2012 Prevenzione e Trattamento della Malattia Cardiovascolare Maddalena Lettino & Marco Cattaneo U.O. Cardiologia Clinica Istituto Clinico Humanitas I.R.C.C.S., Milano & U.O. Medicina III Azienda Ospedaliera San Paolo, Milano

2 Primary and Secondary Prevention of Cardiovascular Disease 23 recommendations for pertinent clinical questions Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted. Pavia Spring Meeting on Thrombosis Giugno 2012

3 Primary Prevention of Cardiovascular Disease 2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B). Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profile if taken over 10 years. In people at moderate to high risk of cardiovascular events, the reduction in MI is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefits will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin. Pavia Spring Meeting on Thrombosis Giugno 2012

4 Ampio database sull uso di LD-ASA nella prevenzione primaria di eventi CVS Trial Popolazione Età (anni) LD-ASA dosaggio Rischio di primo evento CVS a 10 anni WHS (2005) 6 Donne apparentemente sane (n=39,876) mg a giorni alterni 2.5% HOT study Uomini e donne con PAD 100 (1998) 3 115mmHg (n=18,790) mg/die 3.6% PPP (2001) 5 Uomini e donne con 1 fattore di rischio CVS (n=4,495) mg/die 4.3% PHS (1989) 2 Medici maschi apparentemente sani (n=22,071) mg a giorni alterni 4.8% BDT (1988) 1 Medici maschi apparentemente sani (n=5,139) mg/die 8.9% TPT (1998) 4 Uomini ad alto rischio cardiovascolare (n=5,499) mg/die 12.4% BDT, British Doctors Trial; HOT, Hypertension Optimal Treatment; LD-ASA, low-dose acetylsalicylic acid; PHS, Physicians Health Study; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; WHS, Women s Health Study. 1. Peto R, et al. BMJ 1988;296:313 6; 2. Physicians Health Study. N Engl J Med 1989;321:1825 8; 3. Hansson L, et al. Lancet 1998;351: The Medical Research Council s General Practice Research Framework. Lancet 1998;351:233 41; 5. de Gaetano G. Lancet 2001;357: Ridker PM, et al. N Engl J Med 2005;352:

5 Metanalisi: LD-ASA riduce l incidenza di IM non fatale La metanalisi degli studi di prevenzione primaria mostra una riduzione significativa del rischio IM 32 % 24 % BDT, PHS, HOT, TPT, e PPP 1 Riduzione significativa del 32% del rischio di primo IM (p=0.001) BDT, PHS, HOT, TPT, PPP, e WHS 2 Riduzione significativa del 24% del rischio di primo IM (p=0.001) La grandezza della riduzione del rischio è simile a quella osservata negli studi di prevenzione secondaria BDT, British Doctors Trial; HOT, Hypertension Optimal Treatment; LD-ASA, low-dose acetylsalicylic acid; PHS, Physicians Health Study; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; WHS, Women s Health Study. 1. Eidelman RS, et al. Arch Intern Med 2003;163: Bartolucci AA, et al. Am J Cardiol 2006;98:

6 LD-ASA riduce il rischio di coronaropatia Odds ratio e 95% IC BDT PHS TPT HOT PPP WHS Totale La riduzione del rischio di coronaropatia (IM fatale e non fatale e morte per coronaropatia) in favore di LD-ASA (odds ratio 0.77) A favore di LD-ASA A favore di placebo BDT, British Doctors Trial; CHD, coronary heart disease; HOT, Hypertension Optimal Treatment; LD-ASA, low-dose acetylsalicylic acid; MI, myocardial infarction; PHS, Physicians Health Study; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; WHS, Women s Health Study. Bartolucci AA, et al. Am J Cardiol 2006;98:

7 La metanalisi dell Antithrombotic Trialists Collaboration (ATC 2009) è stata condotta con metodica differente dalle precedenti: sono stati analizzati i dati singoli dei pazienti e non i risultati globali per studio. Antithrombotic Trialist (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials.lancet2009;373:1849.

8 Prevenzione primaria Gli studi di prevenzione primaria analizzati sono gli stessi analizzati nella metanalisi del 2006 pubblicata su Am J Cardiol

9 Confronto con metanalisi precedente ATTC 2009 Metanalisi del 2006 I risultati sono in linea con quelli della precedente metanalisi e confermano l efficacia di aspirina a basse dosi in prevenzione primaria.

10 Aspirina è raccomandata per la prevenzione del primo evento cardiovascolare e delle recidive Organizzazione Anno Raccomandazione Prossimo agg. USPSTF Raccomandata nella prevenzione primaria in uomini di età compresa tra anni (primo infarto) e donne di età compresa tra anni (prevenzione dello stroke) ACCP Raccomandata nella prevenzione primaria in pazienti a rischio moderato per eventi coronarici, aspirina mg/die Terapia a tempo indefinito dopo IM, o ACS, e nei pazienti con coronaropatia stabile dopo PTCI ESO Prevenzione secondaria dello stroke in pazienti che non necessitano di anticoagulanti AHA 4 AHA 5 (donne) Raccomandata nei pazienti ad alto rischio ( mg/die), in modo particolare nei pazienti con un rischio per coronaropatia a 10 anni 10% Nelle donne ad alto rischio mg/die se i benefici superano i rischi, salvo controindicazioni WHO Aspirina a basse dosi deve essere somministrata a pazienti con un rischio 30% ESC Aspirina a dosi di mg/die è indicata in tutti i pazienti in prevenzione secondaria (inclusi i diabetici), se non controindicata ACCP: American College of Chest Physicians; ACS: acute coronary syndrome, AHA: American Heart Association; CAD: coronary artery disease; CHD: coronary heart disease; CVD: cardiovascular disease; ESC: European Society of Cardiology; ESO: European Stroke Organisation; MI: myocardial infarction; USPSTF: United States Preventive Services Task Force; WHO: World Health Organization 1. USPSTF. Recommendation statement. Ann Intern Med 2009;150: ACCP. Chest 2008; 133:776S 814S. 3. ESO. Guidelines for management of ischaemic stroke and transient ischaemic attack, AHA. Circulation 2002; 106: Mosca L, et al. Circulation 2007;115: WHO: Prevention of Cardiovascular Disease. Pocket Guidelines for Assessment and Management of Cardiovascular Risk ESC. Eur Heart J 2007;28:

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12 International Diabetes Federation Aspirina mg/die nei pazienti con evidenza di patologia cardiovascolare o ad alto rischio (ad eccezione dei pazienti intolleranti o con ipertensione non controllata)

13 ..Consiglia aspirina ai pazienti con età > 50 anni e ai più giovani con ulteriori fattori di rischio per patologie cardiovascolari, inclusa microalbuminuria. Usa clopidogrel solo nei pazienti con chiara intolleranza all aspirina

14 ESC guidelines 2012

15 Secondary Prevention of Cardiovascular Disease Choice of Long-term Antithrombotic Therapy in Patients With Established Coronary Artery Disease For patients with established CAD (including patients after the first year post-acs and/or with prior CABG surgery): We recommend long-term single antiplatelet therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no antiplatelet therapy (Grade 1A). We suggest single over dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B). Pavia Spring Meeting on Thrombosis Giugno 2012

16 Secondary Prevention of Cardiovascular Disease Definition of patients with established coronary artery disease (CAD): Patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary stenoses >50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnosing testing. Pavia Spring Meeting on Thrombosis Giugno 2012

17 Primary and Secondary Prevention of Cardiovascular Disease Choice of Antithrombotic Therapy Following ACS For patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI): We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily or clopidogrel 75 mg daily plus lowdose aspirin mg daily) over single antiplatelet therapy (Grade 1B). We suggest ticagrelor 90 mg daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B). For patients in the first year after an ACS who have undergone PCI with stent placement: We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily, clopidogrel 75 mg daily plus lowdose aspirin, or prasugrel 10 mg daily plus low-dose aspirin over single antiplatelet therapy) (Grade 1B). Pavia Spring Meeting on Thrombosis Giugno 2012

18 Primary and Secondary Prevention of Cardiovascular Disease Choice of Antithrombotic Therapy Following ACS Remarks: Evidence suggests that prasugrel results in no benefit or net harm in patients with a body weight of less than 60 kg, age above 75 years, or with a previous stroke/tia. Pavia Spring Meeting on Thrombosis Giugno 2012

19 Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis Prior Stroke / TIA Yes No P int = Risk (%) Age >=75 < 75 P int = Wgt < 60 kg >=60 kg P int = OVERALL Prasugrel Better HR Clopidogrel Better -13

20 Primary and Secondary Prevention of Cardiovascular Disease Choice of Antithrombotic Therapy Following ACS We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B). Pavia Spring Meeting on Thrombosis Giugno 2012

21 Cumulative incidence (%) The PLATO study K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke) Completeness of follow-up 99.97% = five patients lost to follow-up Clopidogrel Ticagrelor HR 0.84 (95% CI ), p= No. at risk Ticagrelor Clopidogrel Days after randomisation 9,333 9,291 8,628 8,460 8,219 6,743 5,161 4,147 8,521 8,362 8,124 6,743 5,096 4,047 Wallentin L et al. N Engl J Med 2009; /NEJMoa

22 K-M estimated rate (% per year) The PLATO study Non-CABG and CABG-related major bleeding NS 7.9 Ticagrelor Clopidogre l 7 NS 6 5 p= p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Wallentin L et al. N Engl J Med Sep 10;361(11):

23 Primary and Secondary Prevention of Cardiovascular Disease For patients with ACS who have undergone elective PCI with placement of bare metal stent (BMS): For the first month, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A). For the subsequent 11 months, we suggest dual antiplatelet therapy with combination of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C). After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). Pavia Spring Meeting on Thrombosis Giugno 2012

24 Primary and Secondary Prevention of Cardiovascular Disease For patients who have undergone elective PCI with placement of drug eluting stent (DES) (1): For the first 3 to 6 months, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A). Remarks: Absolute minimum duration will vary based on stent type (in general 3 months for -limus stents and 6 months for -taxel stents). Pavia Spring Meeting on Thrombosis Giugno 2012

25 Primary and Secondary Prevention of Cardiovascular Disease For patients who have undergone elective PCI with placement of drug eluting stent (DES) (2): After 3 to 6 months, we suggest continuation of dual antiplatelet therapy with low dose aspirin 75 to 100 mg and clopidogrel (75 mg daily) until 12 months over single antiplatelet therapy (Grade 2C). After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). Single antiplatelet therapy thereafter is recommended as per the established CAD recommendations (see recommendations ). Pavia Spring Meeting on Thrombosis Giugno 2012

26 Primary and Secondary Prevention of Cardiovascular Disease For patients with CAD undergoing elective PCI but no stent placement: We suggest for the first month, dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C). Single antiplatelet therapy thereafter is recommended as per the established CAD recommendations (see recommendations ). Pavia Spring Meeting on Thrombosis Giugno 2012

27 NSTE ACS ESC guidelines 2011 Prolonged or permanent withdrawal of P2Y12 inhibitors within 12 months after the index event is discouraged unless clinically indicated Class I Level C

28 Primary Endpoint (%) TRITON TIMI 38 Timing of Benefit (Landmark Analysis) 8 Clopidogrel Clopidogrel Prasugrel 4.7 Prasugrel 2 HR 0.82 P=0.01 HR 0.80 P= Loading Dose Days Maintenance Dose

29 Cumulative incidence (%) Cumulative incidence (%) 8 Studio PLATO Primary efficacy endpoint over time (Composite of CV death, MI or stroke) 8 6 Clopidogrel Clopidogrel Ticagrelor 4 Ticagrelor HR 0.88 (95% CI ), p= HR 0.80 (95% CI ), p< Days after randomisation Days after randomisation * No. at risk Ticagrelor 9,333 8,942 8,827 8,763 8,673 8,543 8,397 7,028 6,480 4,822 Clopidogrel 9,291 8,875 8,763 8,688 8,688 8,437 8,286 6,945 6,379 4,751 *Excludes patients with any primary event during the first 30 days Wallentin L et al. N Engl J Med Sep 10;361(11):

30 NSTE ACS ESC guidelines 2011

31 ESC/EACTS Guidelines; Eur Heart Guidelines on myocardial revascularization ESC/EACTS Guidelines; Eur Heart J ; doi: /eurheartj/ehq277

32 ESC/EACTS Guidelines; Eur Heart Guidelines on myocardial revascularization ESC/EACTS Guidelines; Eur Heart J ; doi: /eurheartj/ehq277

33 PRODIGY raises questions about longer clopidogrel duration poststenting End point End point Type 2, 3, or 5 BARC 6-mo dual 6-mo dual antiplatelet therapy (%) 24-mo dual 24-mo dual antiplatelet therapy antiplatelet (%) therapy antiplatelet (%) therapy (%) HR (95% CI) Death/MI/stroke ( ) bleeding p TIMI major bleeding Death ( ) Red blood cell transfusion Death/MI ( ) ESC Congress 2011

34 Primary and Secondary Prevention of Cardiovascular Disease Pavia Spring Meeting on Thrombosis Giugno 2012

35 Primary and Secondary Prevention of Cardiovascular Disease Anterior MI, LV Thrombus, and Stent Placement: For patients with anterior MI and LV thrombus or at high risk for LV thrombus (ejection fraction <40%, anteroapical wall motion abnormality) who do not undergo stenting: We recommend warfarin (INR ) plus low-dose aspirin 75 to 100 mg daily over single antiplatelet therapy or dual antiplatelet therapy for the fi rst 3 months (Grade 1B). Thereafter, we recommend discontinuation of warfarin and continuation of dual antiplatelet therapy for up to 12 months as per the ACS recommendations (see recommendations ). After 12 months, single antiplatelet therapy is recommended as per the established CAD recommendations (see recommendations ). Pavia Spring Meeting on Thrombosis Giugno 2012

36 Primary and Secondary Prevention of Cardiovascular Disease For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection fraction <40%, anteroapical wall motion abnormality), who undergo BMS placement: We suggest triple therapy (warfarin [INR ], low-dose aspirin, clopidogrel 75 mg daily) for 1 month over dual antiplatelet therapy (Grade 2C). We suggest warfarin (INR ) and single antiplatelet therapy for the second and third month post-bms over alternative regimens and alternative time frames for warfarin use (Grade 2C). Thereafter, we recommend discontinuation of warfarin and use of dual antiplatelet therapy for up to 12 months as per the ACS recommendations (see recommendations ). After 12 months, antiplatelet therapy is recommended as per the established CAD recommendations (see recommendations ). Pavia Spring Meeting on Thrombosis Giugno 2012

37 Primary and Secondary Prevention of Cardiovascular Disease For patients with anterior MI and LV thrombus or at high risk for LV thrombus (ejection fraction, 40%, anteroapical wall motion abnormality) who undergo DES placement: We suggest triple therapy (warfarin [INR ], low-dose aspirin, clopidogrel Pavia Spring Meeting on Thrombosis Giugno 2012

38 Primary and Secondary Prevention of Cardiovascular Disease Antithrombotic Therapy in Patients With Systolic LV Dysfunction For patients with systolic LV dysfunction without established CAD and no LV thrombus, we suggest not to use antiplatelet therapy or warfarin (Grade 2C). Remarks: Patients who place a high value on an uncertain reduction in stroke and a low value on avoiding an increased risk of GI bleeding are likely to choose to use warfarin. Pavia Spring Meeting on Thrombosis Giugno 2012

39 Primary and Secondary Prevention of Cardiovascular Disease Antithrombotic Therapy in Patients With Systolic LV Dysfunction For patients with systolic LV dysfunction without established CAD with identified acute LV thrombus (eg, Takotsubo cardiomyopathy), we suggest moderate-intensity warfarin (INR ) for at least 3 months (Grade 2C). For patients with systolic LV dysfunction and established CAD, recommendations are as per the established CAD recommendations (see recommendations ). Pavia Spring Meeting on Thrombosis Giugno 2012

40 Primary and Secondary Prevention of Cardiovascular Disease Pavia Spring Meeting on Thrombosis Giugno 2012