Introduzione all’importanza della doppia antiaggregazione

e del raggiungimento dei target

Cesare Greco

Le modificazioni dell’epidemiologiae le difficoltà dalla prevenzione secondaria

Fox Eur Heart J 2010

68%

86%

97%

STEMI NSTEMI UA

In-H

Post-H

Mortality composition at 5 years follow up

100%

Fox Eur Heart J 2010

Registro IN-ACS OutcomeMortalità intraospedaliera e ad 1 anno:

SCA-NSTE e STEMI

5%

10% 8.6%

2 %

4.4%

STEMI

SCA NSTE

In-H Dimissione 1 anno

15%

9.8%

Rizzello Acute Card Care 2012

X 4X 2

Registro IN-ACS OutcomeReinfarto dalla dimissione ad 1 anno:

SCA-NSTE e STEMI

5%

10%

5.4 %4.3%

STEMI

SCA NSTE

Rizzello Acute Card Care 2012

Registro IN-ACS OutcomeSottoutilizzo dei trattamenti raccomandati alla

dimissione negli STEMI ad alto rischio (non riperfusi)

Pedone Acute Card Care 2009

STEMI Non riperfusi STEMI PCI STEMI Trombolisi

Antiaggreganti 93% 99% 96%

Doppia 58% 94% 63%antiaggregazione

Betabloccanti 71% 83% 75%

Statine 68% 78% 77%

P<0.0001 per tutti

STEMI x 2NSTEMI x4

Total mortality at 6 months follow up

Discharge-30 days 30 days-6 months

BLITZ4 Performance of CCU Adherence to pharmacological therapy

11.706 AMI patients from 163 Coronary Units

Discharge 6 months

BLITZ4 Performance of Centers Process of care

LV function assessment

LDL measurement

Risk stratification

Anti smoke counseling

Cardiac rehabilitation referral

In-Hospital indicators

Post-discharge indicators

30 day and 31–365 day mortality after first time hospitalisation for myocardial infarction between 1984 and 2008

in a Danish nationwide cohort study

Schmidt et al. BMJ 2012

Kostis Circ Cardiovasc Qual Outcomes 2010

Therapeutic Control of Blood Pressure*

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Survey 1 34,4% 39,1% 47,9% 39,7% 44,0% 41,0% 43,3% 37,7% 41,0%Survey 2 47,2% 43,4% 36,7% 29,1% 55,0% 45,7% 43,5% 31,1% 41,2%Survey 3 30,1% 29,1% 44,1% 45,2% 44,1% 34,8% 35,3% 41,4% 38,7%

Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL

P=0.57

S2 vs. S1 : P=0.98S3 vs. S2 : P=0.36S3 vs. S1 : P=0.37

* SBP/DBP < 140/90 mmHg for non-diabetics or < 130/80 mmHg for diabetics

The EUROASPIRE Surveys

Prevalence of Diabetes*

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Survey 1 21,8% 15,4% 16,7% 13,5% 26,6% 17,2% 10,3% 17,4% 17,4%Survey 2 21,5% 18,7% 27,5% 13,5% 21,1% 21,8% 13,2% 23,8% 20,1%Survey 3 30,8% 19,1% 34,2% 22,6% 44,8% 21,7% 20,6% 18,8% 28,0%

Czech Rep. Finland France Germany Hungary Italy Nether-

lands Slovenia ALL

P=0.004

S2 vs. S1 : P=0.21S3 vs. S2 : P=0.02S3 vs. S1 : P=0.001

* Self-reported history of diagnosed diabetes

The EUROASPIRE Surveys

Prevalence of Smoking*

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Survey 1 22,0% 12,8% 25,0% 16,8% 23,3% 18,6% 31,8% 13,3% 20,3%Survey 2 19,3% 21,6% 24,2% 16,8% 30,1% 15,1% 28,3% 14,6% 21,2%Survey 3 22,2% 16,8% 24,8% 18,4% 18,3% 14,0% 15,1% 12,0% 18,2%

Czech Rep. Finland France Germany Hungary Italy Nether-

lands Slovenia ALL

P=0.64

S2 vs. S1 : P=0.83S3 vs. S2 : P=0.37S3 vs. S1 : P=0.48

* Self-reported smoking or CO in breath > 10 ppm

The EUROASPIRE Surveys

Zeymer Eur J Prev Cardiol 2012

DAT administered prior to acute coronary syndrome (ACS) event, at hospital discharge, and at 6- and 12-months

Aderenza, tollerabilità ed efficacia

Interruzione dei trattamenti raccomandati durante il follow-up in pazienti con Pregresso IMA

Dati del registro SIMG - Health Search - JCVM 2009

0%

20%

40%

60%

80%

100%

1 anno 2 anni 3 anni 4 anni 5 anni

ASA Beta-B Statine ACE/ARB

Ho PM,et al Arch. Int. Med. 2006

L’Interruzione precoce delle terapie farmacologiche basate sull’evidenza dopo una SCA è molto frequente

I dati del Registro PREMIER

0

25

50

75

100

0 3 6 9 12Mesi di Follow-up

Pazi

enti

(%)

Aspirina Statine

Beta-bloccanti

Predittori indipendenti di interruzione della terapia

Età avanzata (≥70 anni) Basso livello socio-economico Sesso femminile Mancata effettuazione di PTCA

durante il ricovero Presenza di patologie maggiori

concomitanti

1521 pazienti dimessi dopo IMA

Ho et al. Arch Intern Med. 2006;166:1842-1847

Eur Heart J 2008

Spertus Circulation 2006

Tuppin Arch Cardiovasc Dis 201014,007 patients admitted for MI in the first hal f of 2006

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

http://osservatorioarno.cineca.org

Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta

Aderenza, tollerabilità ed efficacia

Patrono N Engl J Med 2011Patrono et al. for ESC Task Force Eur Heart J 2004

The risk for serious GI bleeding with low-dose ASA is continuous (VALIANT trial)

Dotted lines: 95% CIs of the estimated rateMoukarbel Eur Heart J 2009ASA = acetylsalicylic acid; CI = confidence interval; GI = gastrointestinal

Aspirin leads to suppression of mucosal prostaglandin synthesis and subsequent formation of mucosal erosions

Whereas the inhibition of thromboxane-A2-mediated platelet function is dose independent (at least for daily doses N30 mg), the impairment of PGE2-mediated cytoprotection in the GI mucosa is dose dependent

Patrono et al. for ESC Task Force Eur Heart J 2004

ASA therapy increases the odds of upperGI bleeding

Weil et al. BMJ 1995

Low-dose ASAASA = acetylsalicylic acid; GI = gastrointestinal; NSAIDs = non-steroidal anti-inflammatory drugs.*non-ASA NSAID; **any dose, for less than 1 month

Alternative ASA formulations do not reduce the relative risk of upper GI bleeding

Kelly et al. Lancet 1996

ASA dose ≤ 325 mg/day

Steinhubl for CHARISMA Ann Int Med 2009

(75 or 81)

Primary efficacy end point (CV death, myocardial infarction, or stroke)

Peters Circulation 2003

Aspirin dose and the incidence of major bleeding

*Adjusted for gender, weight, hypertension, components of the TIMI risk score, rates of angiography, PCI and CABG, and the use of NSAIDs, heparin, GP2B3A inhibitors, oral anticoagulants, open-label ticlopidine, or clopidogrel at any time during the study period

Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes:

the CURE Study

Risk of upper GI bleed among low-dose ASA users is reduced by proton pump inhibitor (PPI) use

• 2049 cases of upper GI bleed; 20 000 controls (The Health Improvement Network UK primary care database)

• Current use of PPI for >30 days reduced the risk of upper GI bleed in low-dose ASA users and other at-risk groups

Lin Gastroenterology 2011

Population Risk ratio (95% CI)

All patients 0.80 (0.68, 0.95)

Low-dose ASA users 0.58 (0.42, 0.80)

Dual antiplatelet therapy 0.21 (0.05, 0.87)

NSAID users 0.48 (0.30, 0.77)

Coxib users 0.50 (0.19, 1.33)

Corticosteroid users 0.67 (0.33, 1.36)

Warfarin users 0.48 (0.22, 1.04)

GI problems reported by patients taking low-dose ASA for CV risk management

Moberg C et al. The Patient 2011

ASTERIX randomized study: ulcer incidence

71% reduction inulcer occurrencep=0.0007

1,8

6,2

0

1

2

3

4

5

6

7

Esomeprazole 20 mg od Placebo

Patie

nts

(%) w

ith g

astr

ic

or d

uode

nal u

lcer

Yeomans Am J Gastroenterol 2008

26 weeks

Esomeprazole 20 mg Placebo

ASTERIX study: resolution of upper GI symptoms from aspirin*

Symptom, n/N (%) Esomeprazole20 mg od Placebo P value

Epigastric pain 47/56 (83.9) 28/42 (66.7) 0.05

Epigastric burning 32/44 (72.7) 18/31 (58.1) 0.19Epigastric discomfort 43/63 (68.3) 29/57 (50.9) 0.05

Heartburn 35/39 (89.7) 28/42 (66.7) 0.01

Acid regurgitation 19/22 (86.4) 13/23 (56.5) 0.03

Nausea 25/27 (92.6) 11/14 (78.6) 0.20

Bloating 67/86 (77.9) 41/62 (66.1) 0.11

*Analysis concerns patients with resolution of investigator-assessed upper GI symptoms at 26 weeks, among patients with the symptom at baseline

Yeomans Am J Gastroenterol 2008

Lack of pharmacokinetic interaction between esomeprazole and low-dose ASA

ASA = acetylsalicylic acid

Arithmetic mean plasma concentration–time profiles of ASA (325 mg) and esomeprazole (40 mg) following 5 days’ repeated oral administration, alone and in combination

Niazi Int J Clin Pharmacol Ther 2009

Con

cent

ratio

n (m

mol

/L)

0 2 4 6 8 10 12

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Time (hours)

Esomeprazole aloneEsomeprazole + low-dose ASA

Con

cent

ratio

n (m

mol

/L)

0 1 2 3 4 5 6

25

20

15

10

5

0

Time (hours)

Low-dose ASA aloneLow-dose ASA + esomeprazole

Aderenza, tollerabilità ed efficacia

Perk Eur Heart J 2012

JUPITER - Rx JUPITER - Placebo

LDL-C, livelli raggiunti, mg/dL (mmol/L)

WOSCOPS – PlaceboAFCAPS - Placebo

ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Placebo

LIPID - Rx

4S - Placebo

CARE - Rx

LIPID - PlaceboCARE - Placebo

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Inci

d en z

a d i

ev e

nti

(%)

6

Prevenzione Secondaria

Prevenzione Primaria

Rx - Statin therapyPRA – pravastatinATV - atorvastatin

200(5.2)

PROVE-IT - PRATNT – ATV10

TNT – ATV80

Incidenza di eventi in funzione dei livelli di C-LDL raggiunti nei trial con statine

Jones PH et al. Am J Cardiol 2003;92:152-160

Vari

azio

ne d

el c

oles

tero

lo L

DL

(%)

vs.

bas

ale

10 4020 80

Simvastatina(n=648)

Pravastatina(n=485)

Rosuvastatina(n=473)

Atorvastatina(634)

0

-10

-20

-30

-40

-60

-50

‡†

*

*p<0,002 vs Atorvastatina 10 mg; Simvastatina 10, 20, 40 mg; Pravastatina10, 20, 40 mg†p<0,002 vs Atorvastatina 20, 40 mg; Simvastatina 20, 40, 80 mg; Pravastatina 20, 40 mg‡p<0,002 vs Atorvastatina 40 mg; Simvastatina 40, 80 mg; Pravastatina 40 mg

+8%

+17%

+26%

Riduzione media della colesterolemia LDL ottenuta con rosuvastatina rispetto alle altre statine

Riduzione percentuale del C-LDL in funzionedella dose delle statine (mg)

Studio STELLAR

-46,8-42,7-42.0

-50

-40

-30

-20

-10

0

*

Average change in LDL-C from baseline (%)

Rosuvastatin20 mg

Rosuvastatin40 mg

Atorvastatin80 mg

Primary Endpoint

*p< 0.05 versus atorvastatin 80 mg

Similar results were achieved in all subcategories of ACS Pitt B et al. Am J Cardiol 2012

LUNAR (Limiting UNder-treatment of lipids in ACS with Rosuvastatin)

9,7

11,9

5,6

0

5

10

15

**

Mean change in HDL-C from baseline (%)

Rosuvastatin20 mg

Rosuvastatin40 mg

Atorvastatin80 mg

***

LUNARSecondary Endpoint

**p< 0.01, *** p<0.001 versus atorvastatin 80 mg Pitt B et al. Am J Cardiol 2012

LUNARSafety & Tolerability

VariableRosuvastatin

20 mg/day(n=267)

Rosuvastatin40 mg/day

(n=263)

Atorvastatin80 mg/day

(n=269)

Any Serious AE* 28 (10.5%) 23 (8.7%) 38 (14.1%)

Serious Cardiovascular AE*

9 (3.4%) 5 (1.9%) 6 (2.2%)

Unstable angina 4 (1.5%) 3 (1.1%) 3 (1.1%)Myocardial infarction 5 (1.9%) 2 (0.8%) 2 (0.7%)Cerebrovascular accident 0 0 1 (0.4%)

Withdrawal due to AE 10 (3.7%) 16 (6.1%) 25 (9.3%)Musculoskeletal and connective tissue disorders

5 (1.9%) 6 (2.3%) 17 (6.3%)

Death* 0 2 (0.8%) 1 (0.4%)

*None of the serious adverse effects (AEs), serious cardiovascular AEs or deaths were considered by the investigators to be related to study treatment

Pitt B et al. Am J Cardiol 2012

Antiplatelet Therapy in ACS

0

1 08

Placebo APTC CURE TRITON-TIMI 38Single

Antiplatelet RxDual

Antiplatelet RxHigher

IPA

ASA ASA + Clopidogrel ASA +

Prasugrel- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction in

IschemicEvents

Increase in

Major Bleeds

Placebo APTC CURE TRITON -TIMI 38

8,688

8,763

0 10 20 30

8

6

4

2

0

Cum

ulat

ive

inci

denc

e (%

)

Clopidogrel

Ticagrelor

4.775.43

HR 0.88 (95% CI 0.77–1.00), p=0.045

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,875

8,942

8,763

8,827

Days after randomisation

31 90 150 210 270 330

8

6

4

2

0

Clopidogrel

Ticagrelor

5.28

6.60

8,688

8,673

8,286

8,397

6,379

6,480

Days after randomisation*

HR 0.80 (95% CI 0.70–0.91), p<0.001

8,437

8,543

6,945

7,028

4,751

4,822

Cum

ulat

ive

inci

denc

e (%

)

K-M estimate of primary efficacy endpoint over time (Composite of CV death, MI or stroke)

*Excludes patients with any primary event during the first 30 days

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

20%

Events in PLATO stratified by renal function(A) Primary composite of cardiovascular death, myocardial infarction, and stroke

(B) total mortality

James Circulation 2010

Kohli Circulation 2013

Composite end point CV death, MI, stroke

Composite end point CVD/MI/Stroke/SRI/RI/TIA/ATEKohli Circulation 2013

Composite end points of CVD/MI/Stroke/URKohli Circulation 2013

Kohli Circulation 2013

Kohli Circulation 2013 PLATO major bleeding events.

Valutazione economica: ticagrelor vs. clopidogrel nelle SCA

per un'attesa di vita di 15.3 anni:

morte CV ICER/QALY € 10.621mortalità totale 8.345

Lucioni C, Pharmacoeconomics 2011

Conclusioni

Le modificazioni dell’epidemiologia clinica della fase post acuta delle SCArendono indispensabile rifondare la prevenzione secondaria

Per migliorare i risultati della prevenzione secondaria è necessariopromuovere l’aderenza alla terapia farmacologica e raggiungere i targetterapeutici indicati dalle Linee Guida

La tollerabilità e l’efficacia dei farmaci, in particolare di statine ed antiaggreganti, sono strumenti essenziali per il raggiungimentodegli obiettivi terapeutici e per la riduzione degli eventi