Vavouranakis

Ανταγωνιστές του aidαιμοπεταλιακού υποδοχέα GP IIb/IIIa: Έχουν θέση στην νεώτερη αντιαιμοπεταλιακή φαρμακολογία; Ε. Βαβουρανάκης 1

The Spectrum of Myocardial Ischemia Stable Angina

Unstable Non-ST ST Elevated Angina Elevated MI MI (STEMI) (NSTEMI)

Sudden Death

Acute Coronary Syndromes Thrombus present in the artery

Adapted from Cannon CP. Contemporary Diagnosis and Management of Acute Coronary Syndromes. 2nd ed. Newtown, PA: Handbooks in Health Care Co.; 2008.

2

3

Agents That Inhibit Platelet Activation or Aggregation Epinephrine

Collagen

ADP

Thrombin

Heparin Enoxaparin Bivalirudin Fondaparinux

Ticlopidine Clopidogrel Prasugrel AA Shear stress

Tx A2

ASA Thromboxane synthetase inhibitors

Thromboxane receptor antagonist

Platelet aggregation Adapted from Vorchheimer DA, et al. JAMA. 1999;281(15):1407-1414.

4

5

6

7

8

Evolution of Antiplatelet therapy in ACS ASA 108

Clopidogrel vs. placebo

Prasugrel vs. clopidogrel

- 22%

Reduction in

81

- 20%

Ischeamia - 19%

54

Increase in bleeding

27

+ 60%

+ 38%

+ 32%

0

Placebo

APTC

One antiplatelet

CURE

Double antiplatelet

TRITON-TIMI 38

Agents That Inhibit Platelet Activation or Aggregation Epinephrine

Collagen

ADP

Thrombin

Heparin Enoxaparin Bivalirudin Fondaparinux

Ticlopidine Clopidogrel Prasugrel AA Shear stress

Tx A2

GP IIb/IIIa Inhibitors • Tirofiban • Eptifibatide • Abciximab

ASA Thromboxane synthetase inhibitors

Thromboxane receptor antagonist

Platelet aggregation

Adapted from Vorchheimer DA, et al. JAMA. 1999;281(15):1407-1414.

10

11

12

Mortality is reduced by proportional to the use of IIb/IIIa

13

IIb/IIIa receptor antagonists for STEMI • In considering the use of intravenous glycoprotein (GP), IIb/IIIa receptor antagonists for STEMI much of the evidence favoring the use of these agents was established in the era before dual oral antiplatelet (600 mg)

14

15

16

Tirofiban and Eptafibatide

17

18

19

20

21

Additive benefit by adding clopidogrel on top of Iib/IIIa

22

23

24

25

Which patients will benefit most

For Internal Training Purposes Only

26

27

GP IIb/IIIa blockers vs control in contemporary elective PCI

A new meta-analysis – elective PCI, March 8, 2011 Outcome 30 days

GP IIb/IIIa inhibitor (%)

Control (%)

Relative risk

p

Nonfatal MI

5.1

8.3

0.66 (0.55-0.79)

0.0001

Major bleeding

1.2

0.9

1.37 (0.83-2.25)

0.22

Minor bleeding

3.0

1.7

1.70 (1.28-2.26)

0.0001

Mortality

0.3

0.5

0.70 (0.36-1.33)

0.27

28

ACS patients

29

ACS

30

Routine up stream treatment of no benefit

31

STEMI

IN EARLY PRESENTATION PATIENTS

32

Mortality Reduction at one year by early upstream tirofiban (ON-TIME 2)

33

34

IIb/IIIa are necessary

35

36

37

38

39

40

41

42

43

Trials evaluated GP IIb/IIIa antagonists as adjuncts to oral antiplatelet therapy in the setting of • • •

ON-TIME 2 (2009) BRAVE-3 study HORIZONS-AMI

•

Two meta-analyses of randomized trials were published that compared small-molecule GP IIb/IIIa antagonists with abciximab in STEMI patients undergoing primary PCI

•

“Predictors of Stent Thrombosis After Primary Angioplasty in Acute Myocardial Infarction: TheHORIZONS-AMI Trial,”

•

MULTISTRATEGY was an open-label, multicenter, randomized European trial with a 2-by-2 factorial design that randomized 745 STEMI patients undergoing primary PCI to high-dose bolus tirofiban versus abciximab infusion and sirolimus-eluting stent versus bare-metal stent (BMS)

•

FINESSE

On-TIME 2: Study Design STEMI diagnosed in ambulance or referral center ASA + 600 mg clopidogrel + UFH Placebo

N=984 Jun 2006–Nov 2007

HDB Tirofiban*

Transportation Angiogram

Provisional

PCI center PCI

Angiogram

Tirofiban

*Bolus: 25 µg/kg and 0.15 µg/kg/min infusion. van ‘t Hof AWJ, et al. Lancet 2008 Aug 16;372(9638):537-46

45

On-TIME 2: Endpoints Primary: – Residual ST segment deviation (>3 mm) 1 hour after PCI

Key Secondary: – Combined occurrence of death, recurrent MI, urgent TVR, or thrombotic bailout at 30 days follow-up – Safety (major bleeding)

van ‘t Hof AWJ, et al. Lancet 2008;372(9638):537-46

46

On-TIME 2: Inclusion Criteria • Patients with STEMI who were candidates to undergo primary PCI and met the following criteria: – Symptoms >30 minutes but <24 hours, and – ST-segment elevation of >1 mV in 2 adjacent ECG leads

van ‘t Hof AWJ, et al. Lancet 2008;372(9638):537-46

47

On-TIME 2: Drug Regimens

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008 Aug 16;372(9638):537-46

48

On-TIME 2: Patient Characteristics

Adapted from: van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

49

On-TIME 2: Inclusion Site

• Ambulance • Referral Center • PCI Center (ER)

van ‘t Hof AWJ, et al. Lancet 2008 Aug 16;372(9638):537-46

95% 3% 2%

On-TIME 2: ST-Segment >3 mm Deviation 1 Hour Post-PCI P=.02

% of Patients

50 45 40 36.6

35 30

n=493

Placebo

n=491

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

51

On-TIME 2: Combined Endpoint at 30 Days Death, recurring MI, urgent TVR, and thrombotic bailout P=.013

% of Patients

40 35 30 26

25 n=473

n=477

20

Placebo

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

52

On-TIME 2: Death at 30 Days ITT Population All-cause mortality at 30 days

% of Patients

8 P=.144

6 4

2

2 0

n=477

Placebo

n=473

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

53

On-TIME 2: Thrombotic Bailout P=.002

% of Patients

30.00 26.25 22.50 19.9

18.75 n=473

n=477

15.00

Placebo*

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

54

On-TIME 2: Abrupt Closure

% of Patients

3.0

P=.004

2.3

1.6

0.9 n=477 n=473

0.2

Placebo

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

55

On-TIME 2: Safety Bleeding at 30 Days

Placebo

HDB Tirofiban

% of Patients

10.0 P=.233

7.5 P=.363

5.0 2.5 n=473

n=477

n=477

n=473

0

TIMI Major

TIMI Minor

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

56

On-TIME 2: Net Clinical Outcome at 30 Days Death, Recurring MI, urgent TVR, Stroke, and Major Bleeding

% of Patients

20.00 P=.221

16.25 12.50

9.3

8.75 5.00

n=477

Placebo

n=473

1

HDB Tirofiban

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

57

On-TIME 2: ST Deviation Over Time Placebo (n=493) HDB Tirofiban (n=491)

mm Deviation

20 15

P=.84 14.3

P=.028

14.5 12.1

10.9

10 P=.003 4.8

5

3.6

0

Diagnosis

Pre-angio

60 min

van â&#x20AC;&#x2DC;t Hof AWJ, et al. Lancet 2008;372(9638):537-46

58

On-TIME 2: Mortality at 30 Days by Residual ST-Deviation

% of Patients

8 6

P<.001

4.1

4 2 0 ST Dev <3mm

1

ST Dev >3mm

Hamm C, et al. Presented at: SCAI Annual Scientific Sessions/ACC i2 Summit; April 1, 2008; Chicago, IL. Presentation 413-5.

59

Outcome

ON-TIME 2: 30-day results

Placebo/ Tirofiban p no tirofiban (%) (%) 8.6 5.8 0.043

Death/re-MI/urgent TVR Death

4.1

2.2

0.051

Re-MI

2.3

1.9

0.659

Urgent TVR

4.7

3.0

0.098

Major bleeding

2.9

3.4

0.580

Minor bleeding

4.4

5.9

0.206

Stroke

1.4

0.3

0.031

Net clinical outcome*

11.6

8.0

0.024

*The combined incidence of death, re-MI, urgent TVR, stroke, or major bleeding TVR=target vessel revascularization

ten Berg JM et al. J Am Coll Cardiol 2010; 55:2446â&#x20AC;&#x201C;2455.

For Internal Training Purposes Only

STEMI

IN EARLY PRESENTATION PATIENTS

61

Mortality Reduction at one year by early upstream tirofiban (ON-TIME 2)

62

BRAVE 3 Bavarian Reperfusion AlternatiVes Evaluation-3 Trial

For Internal Training Purposes Only

63

BRAVE 3: Study Design STEMI < 24 hours Randomization N=800 Abciximab (n=401) +

Mean time:

UFH (5000 IU), ASA (500 mg), clopidogrel (600 mg)

-Symptom onset to admission 3.5hrs -Symptom onset to balloon 4.5hrs

Placebo (n=399) + UFH (5000 IU), ASA (500 mg), clopidogrel (600 mg)

Primary PCI

Primary Endpoint: Final Infarct Size* (5-7 days after randomization) Secondary Endpoints: Death, MI, UTVR, Stroke, TIMI Major & Minor Bleeding, and profound thrombocytopenia at 30 days * expressed as a percentage of the left ventricle and measured with single photon emission computed tomography (SPECT)

64

65

BRAVE 3: MACE (30 days) Death, MI, Stroke, and UTVR 10.0

% Patients

7.5 P = 0.39 5.0

5.0 3.8 2.5

0

1 As Presented by Julinda Mehilli, MD, Deutsches Herzzentrum, Technical University, Munich, Germany, at the AmericanCollege of Cardiology (ACC) Annual Scientific Sessions, March 2008

2 66

BRAVE 3: Secondary Endpoints (30 days) 10

Placebo (n=399)

% of Patients

Abciximab (n=401)

P= 0.46 5

P = .53

P = .48 4.5

4.2 3.2

3.3

3.5

2.5

0 Death

Death/MI

As Presented by Julinda Mehilli, MD, Deutsches Herzzentrum, Technical University, Munich, Germany, at the AmericanCollege of Cardiology (ACC) Annual Scientific Sessions, March 2008

Death/MI/Stroke

67

BRAVE 3: Safety TIMI Bleeding Placebo (n=399) 10

Abciximab (n=401)

% of Patients

8 P = .09

6

P = NS 3.7

4 2

1.8

1.8

1.8

0

Major As Presented by Julinda Mehilli, MD, Deutsches Herzzentrum, Technical University, Munich, Germany, at the AmericanCollege of Cardiology (ACC) Annual Scientific Sessions, March 2008

Minor

68

BRAVE 3: Safety 10.0

Profound Thrombocytopenia (platelet count <20,000/ÂľL)

% Patients

7.5 P=.03 5.0

2.5

1.5

0

1 As Presented by Julinda Mehilli, MD, Deutsches Herzzentrum, Technical University, Munich, Germany, at the AmericanCollege of Cardiology (ACC) Annual Scientific Sessions, March 2008

2 69

70

71

72

73

CICERO trial Effects on measures of myocardial perfusion and salvage and coronary patency, IC vs IV abciximab bolusing in primary PCI CICERO: Major results Outcome

Intracoronary abciximab

Intravenous abciximab

p

Complete ST-segment resolution (%)

64

62

0.56

Myocardial blush grade 2/3 (%)

76

67

0.02

Mean enzymatic infarct size (creatine kinase 1214 levels in U/L)

1746

0.008

Major adverse cardiac events (%)

6.1

0.79

5.5

CICERO: Mixed results for intracoronary abciximab in STEMI â&#x20AC;˘ Intracoronary administration of abciximab (ReoPro, Eli Lilly) compared with intravenous administration did not improve myocardial reperfusion as assessed by STsegment resolution â&#x20AC;˘ improve myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size in STEMI patients undergoing primary PCI with thrombus aspiration in the CICERO study.

CICERO: Mixed results for intracoronary abciximab in STEMI • when the patients with blush grade 2/3 were separated out into grade 2 and grade 3, it showed that the grade 3 results were almost identical (34% for intracoronary vs 33% for IV), • "it is only really grade 3 that predicts outcomes.

• cardiac enzymes were reported in only 46% of patients.

76

HORIZONS AMI Harmonizing Outcomes With Revascularization and Stents in AMI

For Internal Training Purposes Only

77

HORIZONS AMI: Study Design N=3602 STEMI patients with symptom onset ≤12 h aspirin + thienopyridine UFH + GP IIb/IIIa inhibitor n=1802

1:1

Bivalirudin (± prov GP IIb/IIIa) n=1800

Primary/deferred PCI/CABG/Med mgmt 1:3*

BMS

1:3*

DES

BMS

DES

Endpoints at 30 days: ITT population, PCI population • Primary: Net adverse clinical events (death/reinfarct/uTVR + major bleeding) Major bleeding (TIMI/GUSTO/CABG/non-CABG/thrombocytopenia) • Secondary: MACE (death/reinfarction/uTVR/stroke) *Stent population: stent thrombosis (definite, probable, acute, subacute) *All stent randomization results are still blinded.

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

78

HORIZONS AMI: Primary Endpoints • At 30-days: – Major bleeding* (not related to CABG) – “Net Adverse Clinical Events”: Combination of major bleeding* or composite of major adverse cardiovascular events, including death, reinfarction, target vessel revascularization for ischemia, and stroke * Major bleeding defined as intracranial or intraocular hemorrhage; bleeding at the access site, with a hematoma that was 5 cm or larger or that required intervention; a decrease in the hemoglobin level of 4 g per deciliter or more without an overt bleeding source or 3 g per deciliter or more with an overt bleeding source; reoperation for bleeding; or blood transfusion.

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

79

HORIZONS AMI: Drug Regimens

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

80

HORIZONS AMI: Patient Characteristics

*

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

*P=.04

81

HORIZONS AMI: Study Medications

* For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.C

82

HORIZONS AMI: Primary Outcome Measures ITT Population

Risk ratio Âą95% CI

Upper boundary for noninferiority accepts up to 25% worse RR (95% CI)

NACE

0.76 (0.63-0.92; P=.005)

ACUITY Major Bleeding

0.60 (0.46-0.77; P<.001)

Study not powered to demonstrate non-inferiority for MACE

MACE

0.99 (0.76-1.30; P=.95)

0 Bivalirudin alone better (n=1800) Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

1

2 UFH + GP IIb/IIIa better (n=1802) 83

HORIZONS AMI: Outcomes at 30 Days Primary PCI Population

For Internal Training Purposes Only

84

HORIZONS-AMI: Primary PCI Outcome Measures at 30 Days Primary PCI Population

25

Bivalirudin monotherapy (N=1678) 20

UFH + GPIIb/IIIa inhibitor (N=1662)

P=.005 P<.001

P=.95

15 12.2 10

9.2

8.5 5.1

5 NACE***

Major bleeding*

5.4

5.4

MACE**

*Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke ***NACE = MACE or major bleeding Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.C

85

HORIZONS AMI: Mortality at 30 Days Primary PCI Population Bivalirudin alone (n=1800)

UFH + GP IIb/IIIa (n=1802)

% of Patients

6.000 4.525

P=.067

P=.045 2.9

3.050 2.0

2.8 1.8

P=1.00

1.575 0.2

0.100 Death

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

Cardiac

Non-Cardiac

86

HORIZONS AMI: ACUTE Stent Thrombosis

For Internal Training Purposes Only

87

HORIZONS AMI: Stent Thrombosis Acute (â&#x2030;¤24 h) P<.001

% of Patients

2.00 1.55

1.3

1.10 0.65

0.3 0.20 Bivalirudin Alone (n=1571)

1

UFH + GP IIb/IIIa (n=1553)

Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

88

HORIZONS-AMI 1-Year Data

For Internal Training Purposes Only

89

HORIZONS-AMI: 1-Year Net Adverse Clinical Events* 20

Bivalirudin alone (n=1800)

18

Heparin + GPIIb/IIIa (n=1802)

18.3%

16

15.7%

NACE (%)

14 12

Diff [95%CI] = -2.6% [-5.1, -0.1]

10

HR [95%CI] = 0.84 [0.71, 0.98]

P=0.03

8 6 4 2 0 0

Number at risk Heparin+GPIIb/IIIa Bivalirudin alone

1800 1802

1

2

3 1559 1499

4

5

6

7

8

Time in Months 1514 1459

9

10

1483 1427

11

12 1343 1281

*MACE or major bleeding (non CABG) Mehran R et al. Presented at Transcatheter Cardiovascular Therapeutics. October, 2008; Washington, DC.

90

HORIZONS-AMI: 1-Year Major Bleeding (non-CABG)

Major Bleeding (%)

12 11

Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

10

9.2%

9 8 7

5.8%

6 5 4

Diff [95%CI] = -3.4% [-5.2, -1.7]

3 2

HR [95%CI] = 0.61 [0.48, 0.78]

1

P<0.0001

2

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1621 1544

1601 1532

1586 1515

Mehran R et al. Presented at Transcatheter Cardiovascular Therapeutics. October, 2008; Washington, DC.

1448 1368

91

MACE (%)

HORIZONS-AMI: 1-Year Major Adverse CV Events* Bivalirudin alone (n=1800)

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Heparin + GPIIb/IIIa (n=1802)

11.9% 11.9%

Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21]

P=0.98

0 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1

2

3 1627 1619

4

5

6

7

8

Time in Months 1579 1573

9

10

1544 1540

11

12 1394 1380

*MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran R et al. Presented at Transcatheter Cardiovascular Therapeutics. October, 2008; Washington, DC.

92

HORIZONS AMI: Mortality* at 1 Year Intent-to-Treat (ITT) Population Bivalirudin alone (n=1800)

UFH + GP IIb/IIIa (n=1802)

% of Patients

10.0 7.5 5.0

P=.029

P=.005 4.8 3.8

3.4 2.1

2.5

P=.67 1.3

1.1

0 Death

Cardiac

Non-Cardiac

*All Kaplan-Meier estimates; all CEC adjudicated Mehran R et al. Presented at Transcatheter Cardiovascular Therapeutics. October, 2008; Washington, DC.

93

HORIZONS AMI: Major clinical outcomes, bivalirudin vs UFH/GP IIb/IIIa End point Major bleeding

Bivalirudin (%)Heparin+GP IIb/IIIaHR (95% CI) (%) 6.9 10.5 0.64 (0.51–0.80)

p <0.001

All-cause mortality 5.9

7.7

0.75 (0.58–0.97)

0.03

Cardiac mortality

2.9

5.1

0.56 (0.40–0.80)

0.001

Reinfarction

6.2

8.2

0.76 (0.59–0.92)

0.04

Stone G.TCT 2010; September 21-25, 2010; Washington, DC For Internal Training Purposes Only

MULTISTRATEGY Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs.

Abciximab With Sirolimus-Eluting Stent or

For Internal Training Purposes Only

95

MULTI-STRATEGY: Objective To evaluate the effect of HDB Tirofiban and sirolimuseluting stents (SES) as compared with abciximab infusion and bare metal stent (BMS) implantation in patients with STEMI undergoing PCI

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

96

MULTISTRATEGY: Study Design STEMI “all-comer” patients •Aspirin + clopidogrel + UFH before arterial sheath insertion •Coronary angiography ± PCI •Stenting was the default strategy in patients with RVD ≥2.5 mm at visual estimation

1:1 HDB Tirofiban*

Abciximab

1:1

SES

1:1

BMS

SES

BMS

*Given as a bolus of 25 µg/kg, followed by an 18- to 24-hour infusion at 0.15 µg/kg/min.

Clinical follow-up at 1, 4, and 8 months; 1 to 5 years Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

97

MULTI-STRATEGY: Inclusion Criteria â&#x20AC;˘ Chest pain for longer than 30 minutes with an ECG ST-segment elevation of > 1mm in > 2 contiguous ECG leads, or with a new left bundlebranch block, and â&#x20AC;˘ Admission either within 12 hours of symptom onset or between 12 and 24 hours after onset with evidence of continuing ischemia

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

98

MULTISTRATEGY: Primary Endpoints • Pharmacology Arm Noninferiority basis – ≥50% Σ ST-segment elevation resolution within 90 min after last balloon inflation @ tt-EKG

• Stent Arm Superiority basis – Cumulative rate of MACE, defined as overall death, reinfarction, or TVR within 8 months Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

99

MULTI-STRATEGY: Drug Regimens

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

100

MULTI-STRATEGY: Patient Characteristics

Adapted from: Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

101

MULTISTRATEGY: Primary Endpoint ≥50% Σ ST segment resolution P<.001 noninferiority P=.53 superiority

% of Patients

90

85.3

H0: 85%

85

n=361

n=361

80 Abciximab

1

HDB Tirofiban

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

102

1° Endpoint >50% ST Segment Resolution Subgroup Analysis PRIMARY END POINT

RISK RATIO (95% CI)

Tirofiban

P-VALUE

Abciximab

Non-inferiority

Superiority

83.6

0.001

0.53

82.3

0.002 0.003

0.55 0.55 0.55

85.3

< 65 yr ≥ 65 yr

86.6 84.5

Male Female

86.0 82.4

81.9 88.5

<0.001 0.37

Diabetes No Diabetes

84.6 85.2

80.0 84.2

0.059 <0.001

Killip class 1 Killip class ≥2

86.5 77.0

84.9 78.9

<0.001 0.22

0.57

Bare Metal Stent Sirolimus-Eluting Stent

84.8 85.9

82.7 84.6

0.002 0.003

0.59 0.74

Single-vessel disease Double-vessel disease Triple-vessel disease

85.2 87.2 84.2

85.8 86.7 72.8

0.02 0.01 0.002

0.86 0.89 0.10

79.6 89.4

71.9 92.1

<0.001 0.01

0.11 0.26

84.7 86.0

88.4 82.0

0.004 0.002

0.95 0.37

85.6 85.8

85.1 76.3

0.001 <0.001

0.89 0.11

Prespecified Non-inferiority Limit

Overall

Anterior Myocardial infarction Non Anterior Myocardial infarction Time to Tx ≤ 4 hr Time to Tx > 4 hr Creatinine Clearance ≥ 60 ml/min Creatinine Clearance < 60 ml/min

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

1.5

1.4

1.3

1.2

1.1

Tirofiban Better

1.0

0.9 0.8

0.7

0.6

% 84.6

0.5

Abciximab Better

0.74

MULTISTRATEGY: 30-Day Outcomes (Pharmacology) MACE (death, reinfarction, and TVR)

% of Patients

10.000 P=.85

8.475 6.950 5.425 n=372

n=372 4

3.900 Abciximab

1

HDB Tirofiban

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

104

MULTISTRATEGY: Death at 30 Days All-cause mortality at 30 days

% of Patients

10.0 7.5 5.0

P=.16

2.5 1.1

n=372

n=372

0 Abciximab

1

HDB Tirofiban

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

105

MULTISTRATEGY: 8-Month Outcomes Pharmacology MACE (death, reinfarction, and TVR) 20.00 P=.30

% of Patients

16.25 12.50 9.9

8.75 n=372

n=372

5.00 Abciximab

1

HDB Tirofiban

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

106

MULTISTRATEGY: Safety Endpoint Thrombocytopenia at 30 days

% of Patients

8.0

(n=372) Abciximab HDB Tirofiban (n=372)

6.1 4.2

P=.004 P=.03

2.3 0.4

Severe

Any

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

107

MULTISTRATEGY: Safety Bleeding at 30 days Abciximab (n=372) HDB Tirofiban (n=372)

% of Patients

10.0

P=.40

7.5 5.0

P=.44

2.5 0

TIMI Major

TIMI Minor

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

108

MULTISTRATEGY: ST Segment Resolution Internal validity assessment of the chosen primary endpoint P=.023 (log rank)

% Death/MI Event-Free Survival

100.000

ST resolution ≥50% 66.667

33.333

ST resolution ≤50% 0

0

50

100

150

200

250

Days After Randomization Valgimigli MC, et al. Presented at: SCAI Annual Scientific Sessions/ACC i2 Summit; April 1, 2008; Chicago, IL. Presentation 413-7.

109

MULTISTRATEGY: Safety Late Stent Thrombosis

â&#x20AC;˘ The rate of late stent thrombosis in this study was extremely low â&#x20AC;˘ No differences in the rates of late stent thrombosis were evident between the HDB Tirofiban and abciximab groups, even in those receiving SES

Valgimigli M, et al. JAMA. 2008;299(15):1788-1799.

110

FINESSE . Facilitated PCI in patients with ST-elevation myocardial infarction.

Ellis SG, et al N Engl J Med.2008;358(21):2205-2217.

•

•

• • •

The hypothesis of this study was that in patients with acute ST segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) preceded by early treatment with abciximab plus half-dose reteplase (combinationfacilitated PCI) or with abciximab alone (abciximab-facilitated PCI) as compared with abciximab administered immediately before the procedure (primary PCI [PPCI])

would result in improved outcomes.

111

The primary endpoint was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomisation, cardiogenic shock, and

112

ACC/AHA UA/NSTEMI: GP IIb/IIIa Inhibitor Dosing

Anderson JL, et al. Circulation. 2007;116(7):e148-e304.

114

National US registry - Adverse events in dialysis patients

Adverse events

Contraindicated antithrombotics (%) In-hospital 5.6 bleeding

Noncontraindicated Odds ratio antithrombotics (95% CI) (%) 2.9 1.93 (1.66–2.23)

In-hospital 6.5 death

3.9

Tsai TT et al. JAMA 2009; 302:2458-2464.

Multivariable adjusted odds ratio (95% CI) 1.66 (1.43–1.92)

1.68 1.24 (1.46–1.95) (1.04–1.48)

National US registry - Adverse events in dialysis patients • One out of five dialysis patients who underwent PCI in recent years received a contraindicated antithrombotic medication and, in doing so, faced significantly increased risk of in-hospital bleeding.

• Compared with dialysis patients who were given alternative antithrombotics, those given agents with a dialysis contraindication or warning in their labeling—eptifibatide and enoxaparin, respectively—were also more likely to die in the hospital.

116

117

118

119

Bleeding

For Internal Training Purposes Only

120

121

No differnce

122

123

124

125

126

127

128

129

130

131

132

133

134

135

Routine up stream treatment of no benefit

136

ACS

137

STEMI

IN EARLY PRESENTATION PATIENTS

138

139

140

141

142

143

144

145

146

148

149

150

151

152

153

154

155

156

157

158

Mortality Reduction at one year by early upstream tirofiban (ON-TIME 2)

159

160

NSTEMI

161

162

GRACE REGISTRUES

163

164

165

166

ACC/AHA STEMI: Recommendations for Antiplatelet Therapy I

A

B

B

IIa IIb

III Aspirin 162 to 325 mg should be given on day 1 of STEMI and in the absence of contraindications should be continued indefinitely on a daily basis there In patients who have undergone diagnostic cardiac catheterization and for whom PCI is planned, clopidogrel* should be started and continued for at least 1 month after bare metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and up to 12 months in patients who are not at high risk for bleeding.

In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days and preferably for 7 days unless the urgency for revascularization outweighs the risks of excess bleeding

Antman EM, et al. J Am Coll Cardiol. 2008 ;51(2):210-47.

*Loading dose not specified

167

ACC/AHA STEMI: Recommendations for Anticoagulation Therapy I

IIa IIb

III Patients undergoing percutaneous or surgical revascularization unfractionated heparin using the following dosages:

C

- No GP IIb/IIIa Inhibitor: 70-100 U/kg bolus targeting ACT 250-350 s - GP IIb/IIIa Inhibitor: 50-70 U/kg bolus targeting ACT 200 s

C

Because of the risk of catheter thrombosis, fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered

C

Bivalirudin may also be used in patients treated previously with UFH for patients undergoing PCI after having received an anticoagulant regimen

Antman EM, et al. J Am Coll Cardiol. 2008 ;51(2):210-47.

168

ACC/AHA STEMI: Recommendations for Antiplatelet Therapy I

IIa IIb

III Clopidogrel 75 mg per day orally should be added to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy.

A

C

In patients <75 who receive fibrinolytic therapy or who do not receive reperfusion therapy, it is reasonable to administer an oral loading dose of clopidogrel 300 mg

Antman EM, et al. J Am Coll Cardiol. 2008 ;51(2):210-47.

169

ACC/AHA STEMI: Long-Term Medical Management • Aspirin 162 to 325 mg daily : – – – –

For at least 1 month after bare-metal stent implantation 3 months after sirolimus-eluting stent implantation 6 months after paclitaxel-eluting stent implantation, After which long-term aspirin use should be continued indefinitely at a dose of 75 to 162 mg daily.

• Clopidogrel 75 mg daily: – PCI – I (B) – no PCI – IIa (C)

• Statin goal:

– LDL-C < 100 mg/dL – I (A) – consider LDL-C < 70 mg/dL – IIa (A)

• Annual influenza immunization – I (B) Antman EM, et al. J Am Coll Cardiol. 2008 ;51(2):210-47.

170

ACC/AHA STEMI: Key Points • Guidelines support rapid evaluation and prompt reperfusion.

• States goal of treating patients with primary PCI within 90 minutes of first medical contact in patients presenting to a hospital with PCI capability.

• Facilitated PCI with full-dose fibrinolytic therapy is not recommended and cited as potentially harmful.

• Anticoagulant therapy: – Supports the use of UF heparin in patients undergoing PCI or CABG. – Notes that in patients undergoing PCI, bivalirudin may also be used in patients treated previously with UF heparin [

171

TACTICS-TIMI 18: Primary Endpoint Death, MI, Rehospitalization for ACS at 30 Days, 6 Months 20

19.4%

Conservative % of Patients

15.9%

(n=1106)

16

P=.025

10.5%

12

Invasive (n=1114)

8

7.4% P=.009

4 0 0

1

2

3

Time (months)

Cannon CP, et al. N Engl J Med. 2001;344(25):1879-1887.

4

5

6 172

Conclusions â&#x20AC;˘

In the setting of dual-antiplatelet therapy with UFH or bivalirudin as the anticoagulant, current evidence indicates that

â&#x20AC;˘

Adjunctive use of a GP IIb/IIIa antagonist can be useful at the time of primary PCI but cannot be recommended as routine therapy.

â&#x20AC;˘

These agents might provide more benefit in selective use, for example, for the patient with a large thrombus burden or for patients who have not received adequate thienopyridine loading.

173

Meta-Analysis of High-Dose Single-Bolus Tirofiban versus Abciximab in Patients Undergoing Percutaneous Coronary Interventions

For Internal Training Purposes Only

174

HDB AGGRASTAT Meta-Analysis: Study Design â&#x20AC;˘ A meta-analysis, using data from 5 trials (n=1,392) comparing high-dose tirofiban with abciximab (TENACITY, Bolognese et al, Danzi et al, Gunasekara et al, Valgimigli et al) was performed, and outcomes assessed at 30 days

Dawson CB, et al. Circulation. 2006;114:II_647.

175

HDB AGGRASTAT Meta-Analysis: Endpoints â&#x20AC;˘ Primary : Composite of death, MI and target vessel revascularization â&#x20AC;˘ Major and minor bleeding and incidence of thrombocytopenia were also assessed.

Dawson CB, et al. Circulation. 2006;114:II_647.

176

HDB AGGRASTAT Meta-Analysis: Composite Endpoint Composite of death, MI and TVR at 30 days P=.46

% of Patients

10.00

8.75

7.50 6.1

6.25

5.00

Abciximab (n=703)

1

HDB Tirofiban (n=689)

Dawson CB, et al. Circulation. 2006;114:II_647.

177

HDB AGGRASTAT Meta-Analysis: 30-Day Outcomes

0

0.5

1.0

Abciximab Better

2.0

3.0

4.0

HDB Tirofiban Better

Dawson CB, et al. Circulation. 2006;114:II_647.

178

HDB AGGRASTAT Meta-Analysis: Safety Abciximab (n=703) HDB Tirofiban (n=689)

20 P=.57

% of Patients

15

15.7

12.8

10 5

P=.54

2.4

P=.26

2.8

1.3

1.3

0

Major Bleed

Minor Bleed

Thrombocytopenia

Dawson CB, et al. Circulation. 2006;114:II_647.

179