Gli inibitori del recettore IIb/IIIa - Cuorediverona.it

P come piastrine, come prezzemolo….. 

Verona,18 Febbraio 2006 

Gli inibitori del recettore IIb/IIIa 

Maurizio Anselmi 

Universita’ degli Studi di Verona

Patogenesi delle Sindromi Coronariche Acute: Ruolo-Chiave 

dell’aggregazione piastrinica nella formazione del trombo 

Rottura di placca 

Adesione delle piastrine 

Attivazione e Aggregazione piastrinica 

Trombosi arteriosa parzialmente 

occludente e Angina Instabile 

o infarto non Q 

Microembolizzazione e Infarto non Q 

MI = myocardial infarction. 

Trombosi coronarica totalmente 

occludente e Infarto Q 

Adapted from Davies. Circulation. 1990;82(supl II):II-38. White. Am J Cardiol. 1997;80(suppl 4A):2B.

Formazione del trombo nelle ACS senza sopraslivellamento del tratto 

ST:l’aggregazione piastrinica è mediata dal recettore GP 2b-3a 

NSTE ACS sono causate da un 

Trombo ricco di piastrine 

Nelle coronarie 

Le piastrine si aggregano fra loro 

mediante il fibrinogeno che forma legami 

con i recettori GP 2b-3a a livello della 

placca 

Unobstructed 

lumen 

GP IIb-IIIa 

thrombus 

platelet 

fibrinogen 

Ruptured 

plaque 

Artery wall 

NSTE = non-ST-segment elevation; ACS = acute coronary syndromes; GP =glycoprotein. 

Adapted from Fintel and Ledley. Clin Cardiol. 2000;23(suppl V):V-1.

GP IIb-IIIa Inhibitors: 

Meccanismo d’ Azione 

Vessel wall 

GP = glycoprotein; vWF = von Willebrand factor. 

Adapted from Fintel and Ledley. Clin Cardiol. 2000;23(suppl V):V-1.

GP IIb-IIIa Inhibitors costituiscono l’unica terapia che blocca l’aggregazione piastrinica in 

risposta allo stimolo esercitato da tutti gli agonisti 

GP = glycoprotein; ADP = adenosine diphosphate; PAR = protease-activated receptor; AA = arachidonic acid; Tx = thromboxane. 

Adapted from Brogan. Ann Emerg Med. 2002;9:1029.

Cardiologia “De Gasperis”- Niguarda, Milano 

9

Cardiologia “De Gasperis”- Niguarda, Milano 

9

(Tirofiban) 

SMALL MOLECULES 

(Eptifibatide) 

(ReoPro)

Inibitori GPIIb/IIIa 

Artist’s conception. 

Piccole molecole 

(blocco competitivo) 

ReoPro ® 

(anticorpo monoclonale)

Recovery of platelet aggregation 

Clinical Considerations: Reversibility 

Platelet 

Aggregation 

100 

80 

60 

40 

20 

● 

● 

▲■ 

● 

● 

▲ 

■ 

● 

■ 

0 

0 6 12 18 24 30 36 

Hours 

■ 

Normal return of platelet function 

■ 

● Tirofiban 

▲ Eptifibatide 

■ Abciximab 

Adapted from Mousa, 1996.

Characteristics of GP IIb/IIIa Inhibitors 

Abciximab Eptifibatide Tirofiban 

Monoclonal 

antibody fragment 

Small molecule Small molecule 

(KGD sequence) (RGD sequence) 

Platelet-Bound Half-life Long (2 hours) Short (secs) Short (secs) 

Plasma Half-life Short (mins) Long (2.5 hs) Long (~2 hs) 

Drug-to-Receptor Ratio 1.5–2.0 250–2,500* >250 † 

% of Dose in Bolus ~75% ‡

Trials Glycoprotein IIb/IIIa 

IIIa inhibitors 

Problematiche 

• Eterogeneita’ studi 

• Diverse molecole, dosaggi 

• Modalita’ somministrazione/evento clinico 

• Rivascolarizzazione si/no 

• End-point 

(combinati) 

• Deduzioni da metanalisi

Patogenesi delle Sindromi Coronariche 

Acute 

NSTE ACS (UA/NSTE MI): 

Trombo parzialmente occludente 

( principalmente piastrinico) 

ST ↑ MI: 

trombo occlusivo (piastrine,globuli 

rossi, fibrina) 

Trombo interno alla placca 

( principalmente piastrine) 

Centro 

della placca 

Trombo interno alla placca 

(principalmente piastrine) 

Centro 

della placca 

NSTE = non-ST-segment elevation; ACS = acute coronary syndromes; UA = unstable angina; MI = myocardial infarction. 

Adapted from Davies. Circulation. 1990;82(supl II):II-38.

Sindromi Coronariche Acute 

ST-segment elevation 

MI 

Non-ST-segment 

elevation ACS



MI 


elevation ACS

UA/NSTEMI e IIb/IIIa 

Riduzione complicanze ischemiche 

(e morte) dopo PCI

8 16 

Lancet 1997; 349:1429-35 

35

Meta-analysis of IIb/IIIa Inhibition in PCI for 30- 

Day Mortality 

EPIC 

EPILOG 

RAPPORT 

CAPTURE 

Impact I 

Impact II 

Restore 

Epistent 

Espirit 

ISAR 2 

Admiral 

Cadillac 

IIb/IIIa Inhibitor Better 

Placebo Better 

N 

2099 

2792 

483 

1265 

150 

4010 

2141 

2399 

2064 

401 

300 

2082 

Ctrl 

1.7 

0.7 

2.1 

1.3 

2.0 

1.1 

0.7 

0.6 

0.6 

4.5 

6.6 

2.3 

Trt 

1.5 

0.4 

2.5 

1.0 

1.0 

0.7 

0.8 

0.5 

0.4 

2.0 

3.4 

1.9 

Combined 

0.73 (0.55,0.96) 

P=.024 

20186 

1.3 

0.9 

0.1 1 10 

OR 

Kong DF, et al. Am J Cardiol. 2003;92:651-655. (with permission)

UA/NSTEMI 

Beneficio solo se PCI

Glycoprotein IIb/IIIa 

IIIa inhibitors without PCI 

Problematiche 

• Pazienti con diverso rischio 

• Diversa % di PTCA in studi (da 2% a 30%) 

• Diversi risultati per abciximab e tirofiban 

• Diversi disegni degli studi 

• Diverse strategie terapeutiche

% of Patients 

IIb/IIIa Inhibition with or without PCI 

Experience with Abciximab in Patients with ACS 

Death or MI through 30 Days 

Invasive Strategy 

25 

20 

15 

10 

5 

0 

83% ↓ 47% ↓ 63% ↓ 73% ↓ 

p = 0.001 p = 0.003 p = 0.001 

10.9 

1.8 

9.0 

4.8 

10.4 

p = 0.001 

14.1 

3.7 3.9 

Medical Rx 

p = NS 

EPIC CAPTURE EPILOG EPISTENT GUSTO IV 

Placebo Abciximab 

ACS 

EHJ 1999; 1 (Suppl. E):E27-E35 Lancet 2001; 357 : 1915-24 

8.0 

8.6

IV GP IIb/IIIa Inhibitors in ACS: Death or MI at 30 

Days (N=31.402 – no elective PCI), 

Study 

Placebo IV Gp IIb/IIIa Odds Ratio 95% CI 

PRISM 7.1% 5.8%* 0.80 0.60-1.06 

PRISM-PLUS 

PLUS 12.0% (*) 8.7% 0.70 0.50-0.98 

0.98 

( † ) 13.6%* 1.17 0.80-1.70 

PARAGON-A 11.7% (l) 10.3% 0.87 0.58-1.29 

(h) 12.3% 1.06 0.72-1.55 

PURSUIT 15.7% (l) 13.4% 0.83 0.70-0.99 

0.99 

(h) 14.2% 0.89 0.79-1.00 

PARAGON-B 11.4% 10.6% 0.92 0.77-1.09 

GUSTO-IV 

8.0% (24h) 8.2% 1.02 0.83-1.24 

(48h) 9.1% 1.15 0.94-1.39 

Overall 11.8% 10.8% t 0.91 0.85-0.98 

0.98 

0 1.0 2.0 

Gp IIb/IIIa Better 

* Without heparin. † With/without heparin. (l), Low dose; (h), High-dose. 

Boersma E, et al. Lancet. 2002;359:189-198. 

Placebo Better 

P=.015

GP IIb/IIIa Inhibitor During Medical Management 

and After PCI: CAPTURE, PURSUIT, PRISM- 

PLUS 

Medical Rx 

Post PCI 

Death or MI 

10% 

8% 

6% 

4% 

2% 

N=12,296 

P=.001 

Control 

GP IIb/IIIa inhibitor 

4.3% 

2.9% 

N=2754 

P=.001 

8.0% 

4.9% 

0% 

0 

Boersma E, et al. Circulation. 1999;100:2045-2048 

+24 h +48 h +72 h +24 h +48 h 

PCI

IIb/IIIa: 

Strategia upstream o downstream

Peterson E.D.et al.: Early use of glycoprotein IIb-IIIa inhibitors in non-ST-elevation 

acute myocardial infarction. 

JACC 2003; 42: 45-53.

ISAR-COOL - Trial design - 

High Risk ACS (n=410) 

(ST depression/Troponin +) 

Pre-load Tirofiban + 

Pre-load Clopidogrel 

72-120 hours 

cooling-down 

Early PCI < 6hs 

(median 2.4 hs) 

Late PCI 

(median 86 hs) 

30-day follow-up

ISAR-COOL study - Pre-procedural outcome 

8% 

Time of PCI 

ISAR-COOL 

Late PCI 

Pre-PCI PCI event-rate 

P=0,002 

Death/MI before PCI 

7% 

6% 

5% 

4% 

3% 

2% 

1% 

ISAR-COOL 

Early PCI 

2,4 hr 

PRISM-PLUS 

TACTICS 

invasive 

25 hr 

71 hr 

86 hr 

0,5% 

1,1% 

2,4% 

6,2% 

0% 

Rand +24hr +48hr +72hr +96hr 

ISAR-COOL 

Early 

TACTICS PRISM-PLUS ISAR-COOL 

Late 

Neumann, JAMA 2003

Messaggio 

Conta il rischio!

CAPTURE 

Results by Troponin T Status 

Death or Nonfatal MI through 6 Months 

% of Pts., Death/MI 

10 

8 

6 

4 

2 

TnT < 0.2 ng/ml - 6 Months 

Placebo 

n=686 

Abciximab* 

30 

25 

20 

15 

10 

5 

TnT > 0.2 ng/ml - 6 Months 

Placebo 

Abciximab* 

64% ↓ 

p = 0.005 

0 

0 

0 30 60 90 120 150 180 0 

Days 

* 0.25 mg/kg bolus followed by a 10 ug/min infusion until PCI; 

continue infusion for 1 hour post-PCI 

022200.1Budden os 3 

30 

60 90 120 150 180 

Days 

Circulation 2000; 101:570-80

TIMI Risk Score For UA/NSTEMI 

• Age ≥ 65 years 

C Statistic=0.65 

χ2 trend P50 % 

• ST deviation 

• ≥ 2 anginal 

events ≤ 24 hours 

• ASA in last 7 days 

• Elevated cardiac 

markers (CK-MB or 

troponin) 

D/MI/Urg Revasc (%) 

50 

40 

30 

20 

10 

0 

40.9 

26.2 

19.9 

13.2 

8.3 

4.7 

0/1 2 3 4 5 6/7 

Number of Risk Factors 

Population (%): 4.3 17.3 32.0 29.3 13.0 3.4 

Antman EM, et al. JAMA. 2000;284:835-442

GP IIb/IIIa Inhibition in Diabetics 

30-Day Mortality in Diabetic Patients 

Trial N Odds Ratio & 95% Cl Placebo IIb/IIIa 

PURSUIT 

2163 

P=.33 

6.1% 

5.1% 

PRISM 

687 

P=.07 

4.2% 

1.8% 

PRISM-PLUS 

362 

P=.17 

6.7% 

3.6% 

GUSTO IV 

1677 

P=.022 

7.8% 

5.0% 

PARAGON A 

412 

P=.51 

6.2% 

4.6% 

PARAGON B 

1157 

P=.93 

4.8% 

4.9% 

Pooled 

6458 

P=.007 

6.2% 

4.6% 

0 0.5 1 1.5 2 

Breslow-Day: P=.50 IIb/IIIa Better Placebo Better OR=0.74 

Roffi M, et al. Circulation. 2001;104:2767-2771. (with permission)

Gli inibitori GP IIb/IIIa 

IIIa riducono 

la mortalità nei pazienti diabetici ! 

La mortalità in questi pazienti si riduce 

complessivamente del 26% (p=0,007) 

Ciò si traduce in: 

1 vita salvata 

ogni 

63 pazienti trattati

Gli inibitori GP IIb/IIIa 

IIIa riducono 

la mortalità nei pazienti diabetici 

sottoposti a PTCA durante l’ospedalizzazione ! 

Costoro rappresentano il 20% dei diabetici. 

La mortalità in questi pazienti si riduce 

complessivamente di ben il 70% (p=0,002) 

Ciò si traduce in: 

1 vita salvata 

ogni 

36 pazienti 

rivascolarizzati per via percutanea

SCA: UA/NSTEMI 

Le linee guida

ESC PCI guidelines 2004 

2004 Recommendations for UA/NSTEMI 

UA/NSTEMI 

ASA/Clopidogrel/UFH 

Nitrate, Betablocker (ACE-inhibitor, Statin) 

high or intermediate risk 

low risk 

Initially planned 

Invasive Strategy 

Initially planned 

Conservative Strategy 

No Upstream 

GPIIb/IIIa inhibitor 

With Upstream 

GPIIb/IIIa inhibitor 

Tirofiban or 

Eptifibatide up to 72 hrs 

Early noninvasive stress testing 

PCI 

Abciximab or 

Eptifibatide 

PCI 

+ continuing Tirofiban 

or Eptifibatide 

PCI 

+/- Abciximab 

or Eptifibatide 

Medical 

Treatment


2004 Recommendations for anti-thrombotic 

thrombotic 

medications for PCI in UA/NSTEMI 

Procedure 

ASA 

Clopidogrel 

Indication 

All procedures 

Immediately (if clinically justifiable) and prolonged for 9-12 

months 

Recommendation 

I C 

I B 

Studies for 

Level A or B 

- 

CURE 

GP IIb/IIIa 

inhibitor 

Abciximab 

Immediately before PCI in high-risk ACS 

I A 

CAPTURE, EPIC 



Eptifibatide 

Immediately before PCI in high-risk ACS 

I C 

- 



Tirofiban, 

Eptifibatide 

“Upstream” in high-risk ACS: pretreatment (48-72 hrs) before 

angiography and PCI 

I C 

- 

Enoxaparin 

Bivalirudin 

Replacement for UFH in high-risk NSTE-ACS, if invasive 

strategy is not applicable 

Replacement for UFH (± GP IIb/IIIa inhibitors) to reduce 

bleeding complications 

I C - 

II a C -

SCA: UA/NSTEMI 

L’applicazione delle linee guida

Guidelines Applied in Practice (GAP) Project 

Quality Improvement Program involving 

2857 Elderly patients treated in 33 hospitals 

Reduction in-hospital, 30-day and one-year mortality before and after GAP project 

End Point 

Before GAP 

After GAP 

P 

In Hospital Mortality 

13,6 

10,4 

0,017 

30 Days Mortality 

21,6 

16,7 

0,001 

1 Year Mortality 

38,3 

33,2 

0,004 

Eagle, Oral at ACC 2004

Coronarografia in base a età 

e TIMI Risk score 

100- 

90- 

80- 

70- 

60- 

50- 

40- 

30- 

20- 

10- 

0- 

71 

71 

65 

62 

42 

75 anni 

44 

TRS 

0-3 

4-7

Possibili motivi di non adesione alle Linee Guida 

nella gestione delle Sindromi Coronariche Acute 

1. Scarsa credibilità delle Linee Guida 

2. Le linee guida sono basate sui risultati 

di trial che non riflettono il mondo reale 

3. Effetto dei nuovi trattamenti è modesto, 

anche se “statisticamente significativo” 

4. Beneficio dei nuovi trattamenti 

dimostrato solo su endpoint surrogati 

5. Non disponibilità del laboratorio 

di emodinamica 

6. Costi insostenibili 

Motivo 

Commento 

1. Sospetto di “conflitto di interessi” 

2. I registri dimostrano incidenze di eventi 

simili a quelle dei trial 

3. E’ una regola generale dei progressi 

terapeutici attuali 

4. Molti endpoint surrogati sono predittori 

di mortalità o altri eventi “hard” 

5. Necessità che più ospedali si organizzino 

“in rete” come per STEMI 

6. Riallocazione di risorse verso procedure 

e trattamenti di dimostrata efficacia 

Savonitto & Klugmann, Ital Heart J Suppl 2004;5:167-176 

176



MI 


elevation ACS



MI 


elevation ACS

Occlusive thrombus contains Fibrin and Platelets

Fisiologia delle sindromi coronariche acute 

Aterosclerosi 

Rottura della placca 

Effetti locali 

Trombosi 

Ostruzione 

Danno macrovascolare 

Conseguenze a distanza 

Embolia Trombosi Vasospasmo 

Danno microvascolare

Abciximab Improves ST Res-90 min 

ST Resolution (%) 

100 

80 

60 

40 

20 

0 

Complete Resolution 

With Abciximab 

37 

Alteplase 

(n=125) 

P

Abciximab During Primary Stenting 

Global LVEF in 2 Randomized trials 

100% 

80% 

60% 

40% 

54% 

P=0.04 

57% 

Control 

Abciximab 

P=0.05 

P=0.003 

61% 62% 

57% 55% 

20% 

0% 

ADMIRAL (n=246) ADMIRAL (n=246) ISAR-2* (n=151) 

24 hours 6 Months 14 days 

*Circulation 1998;98:2695-701, ADMIRAL NEJM 2001;344:1895-903

RAPPORT, ISAR 2, ADMIRAL, CADILLAC 

30 Days Composite Endpoint - Death, MI, or Urgent TVR 

Placebo or No Abciximab 

Abciximab 

Incidence (%) 

20 

15 

10 

5 

↓ 51% 

p=0.03 

11.2 

5.8 

↓ 53% 

p=0.04 

10.5 

5.0 

↓ 52% 

p=0.02 

15.3 

7.3 

↓ 30% 

p=0.04 

7.1 

5.0 

0 

RAPPORT 

(n=483) 

ISAR-2 

(n=401) 

ADMIRAL 

(n=300) 

CADILLAC 

(n=2082) 

RAPPORT Circ 1998; 98: 735, ISAR-2 JACC 2000; 35:915, ADMIRAL NEJM2001;344:1895-903, CADILLAC Stone TCT 2000

A C E 

ONE-YEAR SURVIVAL 

Kaplan-Meier 

100 

Survival (%) 

95 

90 

Stenting plus Abciximab 

p=.043 

95 ± 2 

89 ± 2 

85 

Stenting Alone 

80 

0 30 60 90 120 150 180 210 240 270 300 330 360 

Time (days)

5 GPIIb/IIIa inhibitors trials in Primary Angioplasty 

(all are ReoPro Trials) 

Significant reduction 

of death, reMI or 

TVR at 30 days 

Significant reduction 

of death, reMI at 30 days 

(A) 

(B) 

Death, reinfarction, and target vessel revascularization (TVR) 

at 30 days. Two trials included stroke in the composite end 

point (ACE, CADILLAC), but the incidence was quite low. 

Death or reinfarction at 30 days. 

Topol, JACC 2004;42:1886–9


2004 Recommendations for anti-thrombotic 

medications for PCI in STE-ACS 

Procedure 

ASA 

Indication 

All STE-ACS 

Recommendation 

I B 

Studies for 

Level A or B 

ISIS-2 

Clopidogrel 

After all stent procedures up to 4 weeks 

I C 

- 


with PCI 

Abciximab 

All Primary PCI if stenting is not performed 

II a B 

CADILLAC 


with PCI 

Abciximab 

All Primary PCI with routine stenting 

(preferably in high-risk patients) 

II a A 

ADMIRAL, ACE

BMS and abciximab display a 

synergistic role in primary PCI 

setting and… 

“should be currently regarded as the 

gold standard for STEMI” 

B M S D E S 

Medical Costs 

Università degli Studi di Ferrara - Cattedra di Cardiologia

BMS and abciximab display a 

synergistic role in primary PCI 

setting and… 

“should be currently regarded as the 

gold standard for STEMI” 

Abciximab 

Tirofiban 

B M S D E S 

Medical Costs 


Study design 

Inclusion Criteria: STEMI all comers: shock, elderly included 

Exclusion Criteria: Contraindications to Gp IIb/IIIa 

Tirofiban SHDB 

Cypher 

STEMI 

UFH - ASA 

Clopidogrel 

Abciximab 

stand. regimen 

BMS 

CCU 

Cath-Lab 

Valgimigli et al. Cardiovasc Drugs Ther 04; 18: 225-30 


% 

50 

45 

40 

35 

30 

25 

20 

15 

10 

5 

P=0.043 

0 

8-Month 

Outcome 

n=175 

Abciximab+BMS 

P=0.004 

Tirofiban+SES 

P=0.01 

P=0.8 P=0.6 

P>0.99 

P=0.005 

50% 

9% 

19% 

MACE Death MI TVR CVA BR 1° EndPoint 

Valgimigli et al. JAMA 2005; 293: 2109-117 

36% 


Multi-STRATEGY 

MULTIcenter evaluation of Single High Dose 

Bolus TiRofibAn vs. Abciximab and Sirolimus 

EluTing StEnt vs. Bare Metal Stent in 

Acute MYocardial infarction 

Sample size: 

600 patients 

C/E analysis for EU and 

US Market 

Ferrara 

Verona 

Brescia 


STEMI 

IIb/IIIa con trombolitico, senza PTCA

GUSTO V AMI 

GUSTO V - Trial Schematic (n = 16,588) 

ST ↑, lytic eligible, < 6 h 

ASA 

No Abciximab 

2 x 10 U bolus (30’) 

Reteplase 

Standard Heparin: 

5,000 U bolus followed by either 

800 U/hr (pts < 80 kg) or 

1,000 U/hr (pts ≥ 80 kg) infusion 

Abciximab 

2 x 5 U bolus (30’) 

Reteplase 

Low Dose Heparin: 

60 U/kg bolus 

followed by a 

7 U/kg/h infusion 

1º endpoint: mortality at 30 days 

2º endpoint: clinical and safety events at 30 days 

Lancet Lancet 2001; 2001; 357:1905-14

GUSTO V AMI 

Primary Endpoint: 30 Days Mortality 

5.9% 

5.6% 

% Mortality 

• p = 0.43 for superiority 

• Non-Inferiority RR 0.95 

(95% CI, 0.84-1.08) 

Std. Reteplase (n = 8260) 

Abciximab + ↓ Dose Reteplase (n = 8328) 

Days 

Lancet 2001; 357:1905-14

IIb/IIIa 

Varie...ed eventuali

Oral GPIIb/IIIa Inhibitors & Mortality 

Oral GPIIb/IIIa Inhibitor Clinical Trial Results 

% Mortality 

5 

4 

3 

2 

1 

0 

Sibrafiban Sibrafiban 

Roxifiban Xemilofiban 

Orbofiban 

Placebo 

Treatment 

4.4 

4.4 

3.1 

3.1 

2.4 

2.4 

2.0 

1.8 

2.0 

1.8 

1.7 

1.7 

1.5 

1.3 

1.5 

1.3 

1.0 

1.0 

0.7 

0.7 

0 

SYMPHONY 1 SYMPHONY 2 Roxifiban EXCITE OPUS 

OPUS 

90 days 

90 days 

6 months 

7 months 

300 days 

(n = 9,169) 

(n = 6637) 

(n = 464) 

(n = 7,232) 

(n = 10,302) 

SYMPHONY 1: 1: Lancet 2000; 355:337-45, SYMPHONY 2: 2: Oral presentation, ACC 2000, EXCITE: NEJM 2000; 

342:1316-24, Roxifiban: JACC; 2000; 35:Suppl A (Abstract), OPUS: Circ. 1999; 100:I-498 (Abstract)

IIb/IIIa e PCI: 

Nei pazienti stabili

ISAR-REACT: 30 Day Endpoints 

6 

Death/MI/Urgent TVR (%) 

P=.82 

6 

Death (%) 

P=NS 

6 

Urgent TVR (%) 

P=NS 

4 

4.2 

4.0 

4 

4 

2 

2 

2 

0.3 0.3 

0.9 

0.7 

0 

Abciximab 

Placebo 

0 

Abciximab 

Placebo 

0 

Abciximab 

Placebo

Conclusioni 

Glycoprotein IIb/IIIa 

IIIa inhibitors 

• Cardini terapia ACS 

• Sottogruppi (diabete!) 

• Complementari a PCI 

• Sotto-utilizzati 

nel “mondo reale” 

• Da definire l’ottimale strategia

Gli inibitori del recettore IIb/IIIa - Cuorediverona.it

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