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