STEMI Oct. 31, 2011 Core Curriculum
Adjunctive/Conjunctive pharmacological therapy
Robert C. Welsh, MD, FRCPCAssociate Professor, University of Alberta
Director, Adult Cardiac Catheterization and Interventional CardiologyCo-Director, University of Alberta Chest Pain Program
Co-Chair, Vital Heart Response
DisclosuresDisclosures
Research funding: ‐ Abiomed, Astra Zeneca, Boringher Ingelheim, BMS, gEli
Lilly, Johnson and Johnson, Pfiser, Portola, Regado, Roche, sanofi aventis
Consultant/honorarium:‐ Astra Zeneca, Bristol Myers-Squibb, Eli Lilly, Medtronic,
Roche, sanofi-aventis
2
How do you assess patient risk in STEMI?
CRUSADE bleeding risk score GRACE ACS risk model
Baseline HCT 0.34 Elevated cardiac markers +
ST segment deviation +
GFR (Cockcroft Gault) 58 Creatinine 82
Heart Rate 58 Heart Rate 58
Systolic BP 155 Systolic BP 155
Prior vascular disease -
Diabetes Mellitus -
Heart Failure - Heart Failure -
Sex F age 80
Cardiac arrest on admission -
CRUSADE bleeding score = 40 Risk of in-hospital major bleeding 9.2%
GRACE risk score – in-hospital death = 6%In-hospital death or MI = 21%
21
9.2
0
5
10
15
20
25
Ischemia riskIn-hospital death and re-MI
Bleeding riskIn-hospital major bleeding
Baseline risk estimates
Dilemma Balancing Ischemic and Bleeding Risks
Armstrong & Welsh JACC Int, Dec. 2010.
21
9.2
13 15.5
0
5
10
15
20
25
Ischemia riskIn-hospital death and re-MI
Bleeding riskIn-hospital major bleeding
Baseline risk estimates
Intervention risk/benefit estimates
Armstrong & Welsh JACC Int, Dec. 2010.
Dilemma Balancing Ischemic and Bleeding Risks
Anti-thrombotic therapy in STEMI
What is the ‘optimal’ anti-thrombotic agent in patients with STEMI undergoing:
1. Primary PCI
2. Fibrinolysis
3. Receiving no reperfusion
OASIS OASIS –– 6 Trial: Study Design6 Trial: Study Design
Primary Endpoint: Composite of death or reinfarction at 30 daysSecondary Endpoint: Composite of death or reinfarction at 9 days and at
final follow-up
Primary Endpoint: Composite of death or reinfarction at 30 daysPrimary Endpoint: Composite of death or reinfarction at 30 daysSecondary Endpoint: Composite of death or reinfarction at 9 daysSecondary Endpoint: Composite of death or reinfarction at 9 days and at and at
final followfinal follow--upup
12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial)
Randomized. Blinded. Factorial.28% female, mean age 62 years, mean follow-up 3-6 months
12,092 patients presenting with STEMI within 24 hours of symptom12,092 patients presenting with STEMI within 24 hours of symptom onset onset (shortened to 12 hours of symptom onset midway through trial)(shortened to 12 hours of symptom onset midway through trial)
Randomized. Blinded. Factorial.Randomized. Blinded. Factorial.28% female, mean age 62 years, mean follow28% female, mean age 62 years, mean follow--up 3up 3--6 months6 months
Stratum 1 (No UFH)Stratum 1 Stratum 1 (No UFH)(No UFH) Stratum 2 (UFH)Stratum 2 (UFH)Stratum 2 (UFH)
Fondaparinux2.5mg/day for up to 8
days or hospital discharge
FondaparinuxFondaparinux2.5mg/day for up to 8 2.5mg/day for up to 8
days or hospital days or hospital dischargedischarge
PlaceboPlaceboPlacebo Fondaparinux 2.5mg/day for up to 8
days or hospital discharge
Fondaparinux Fondaparinux 2.5mg/day for up to 8 2.5mg/day for up to 8
days or hospital days or hospital dischargedischarge
UFHUFHUFH
JAMA. 2006 Apr 5;295(13):1519JAMA. 2006 Apr 5;295(13):1519--30. Epub 2006 Mar 14. 30. Epub 2006 Mar 14.
OASIS – 6 Trial: Primary Endpoint OASIS – 6 Trial: Primary Endpoint Reduction in Death/MI: Stratum 1Reduction in Death/MI: Stratum 1
(No UFH indicated)(No UFH indicated)p<0.05p<0.05
Reduction in Death/MI: Stratum 2Reduction in Death/MI: Stratum 2(UFH Indicated)(UFH Indicated)
p=NSp=NS
••There was no difference in Stratum 2, comparing There was no difference in Stratum 2, comparing those patients who received Fondaparinux vs those those patients who received Fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)
p=0.97p=0.97
JAMA. 2006 Apr 5;295(13):1519-30. Epub 2006 Mar 14.
OASIS - 6 Trial: PCI Sub-study at 30 DaysOASIS OASIS -- 6 Trial: PCI Sub6 Trial: PCI Sub--study at 30 Daysstudy at 30 DaysPrimary Endpoint = Death or MI
p=0.19Guiding Catheter Thrombosis
p<0.001
JAMA. 2006 Apr 5;295(13):1519-30. Epub 2006 Mar 14.
ExTRACT–TIMI 25: Study profile
Enox 9.9%
UFH 12.0%
RRR = 17%P < 0.001
ExTRACT–TIMI 25 (N = 20,479)
PCIby 30 days(n = 2,272)
PCIby 30 days
(n = 2,404)
Enoxaparin(n = 10,256)
UFH(n = 10,223)
0
3
6
9
12
15
0 5 10 15 20 25 30
De
ath
/MI
(%)
Antman EM, et al. N Engl J Med 2006;354:1477-1488. Gibson CM, et al. J Am Coll Cardiol 2007;49:2238-2246.
RRR = 23%P = 0.001
Enox 10.7%
UFH 13.8%
0
3
6
9
12
15
0 5 10 15 20 25 30
De
ath
/MI
(%)
Days
Days0 5 10 15 20 25 30
Dea
th o
r MI (
%)
RR 0.77
ORadj 0.72
95% CI 0.60-0.87 (p=0.001)
Adjusted for age, prior ASA use, time to PCI, smoking, time from symptom onset to lytic, type of lytic and propensity to undergo PCI
13.8%UFH
ENOX 10.7%
0
5
10
15
Primary Endpoint - PCI cohort30 day death or MI
Major bleeding: enox 1.4% vs. 1.6%, NS
Net clinical benefit: death/nonfatal MI/nonfatal major bleedEnox 11.5% vs. 14.8%, p<0.001 (0.78 (0.67 – 0.90))
ExTRACT Parent trial bleeding
Major bleeding (including ICH): 211 (2.1) vs. 138 (1.4) 1.53 (1.23–1.89) <0.001ICH: 84 (0.8) vs. 66 (0.7) 1.27 (0.92–1.75) 0.14
Minor bleeding: 260 (2.6) vs. 184 (1.8) 1.41 (1.17–1.70) <0.001Major or minor bleeding: 464 (4.6) vs. 315 (3.1) 1.47 (1.28–1.69) <0.001
Gibson et al, JACC 2007, Antman et al, NEJM 2006
STEMI < 6 hLytic EligibleSTEMI < 6 hLytic Eligible
Double-blindDouble-dummy
ASALytic Choice by MD(TNK, tPA, rPA, SK)
ExTRACTExTRACT--TIMI 25 TRIALTIMI 25 TRIAL
Antman EM et al. Am Heart J, 2005
Enoxaparin< 75 y: 30 mg IV bolus
sc 1.0 mg/kg q 12h (Hosp DC)> 75 y: No bolus
sc 0.75 mg/kg q 12h (Hosp DC)
Enoxaparin< 75 y: 30 mg IV bolus
sc 1.0 mg/kg q 12h (Hosp DC)> 75 y: No bolus
sc 0.75 mg/kg q 12h (Hosp DC)
UFHbolus 60 U/kg
Inf 12 U/kg/h for > 48 h
UFHbolus 60 U/kg
Inf 12 U/kg/h for > 48 h
Day 30Primary Efficacy Endpoint: Death / MI
Primary Safety Endpoint: TIMI Major Hemorrhage
Day 30Primary Efficacy Endpoint: Death / MI
Primary Safety Endpoint: TIMI Major Hemorrhage
WEST Anti-Xa sub-study Results: 1st anti-Xa sample fibrinolysis arm
Note: all times are presented as median values
0.48 U/ml179 min.
0.42U/ml
0.65 U/ml
875 min.153 min.
Total study population N=45
<0.5 U/ml157 min.
186 min.139 min.
Sub-therapeutic N=23
2.6 hours
>0.5 U/ml645 min.
1196 min.178 min.
Therapeutic N=21
10.75 hours
Welsh et al, CJC (abstract), 2007
Fibrinolysis with sq enox (1mg/kg) only
10.8
2.31.6
0.5 0.71.1 1.4
9
12.8
10.9
0
2
4
6
8
10
12
14
Bivalirudin vs UFH with SK for STEMI
Pe
rce
nt
of
pa
tie
nts
p = 0.001
Death ReMI96 H
p = 0.07
Severe Mod Mild
p = 0.05
p <0.001
Lancet 358:1855,2001
p = NS
Bleeding
UFH
Bivalirudin
HORIZONS-AMI main results
Stone G et al, NEJM, May 2008
HORIZONS-AMI main results
Stone G et al, NEJM, May 2008
ATOLL Trial design
STEMI Primary PCI
1° EP: Death, Complication of MI, Procedure Failure, Major Bleeding
Main 2° EP: Death, recurrent MI/ACS, Urgent Revascularization
30 days
Randomization as early as possible (MICU +++)Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before Rx
Similar antiplatelet therapy in both groups
ENOXAPARIN IV0.5 mg/kg
with or without GPIIbIIIa
UFH IV 50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa(Dose ACT-adjusted)
IVRS
Primary PCI
ENOXAPARIN SC UFH IV or SC
Primary EndpointDeath, Complication of MI, Procedure Failure or
Major Bleeding
33.7
28
0
5
10
15
20
25
30
35
40
UFHENOX
RRR = 17% P = 0.07
% of patients
Main Secondary Endpoint (ischemic) Death, Recurrent MI/ACS or Urgent
Revascularization
0 5 10 15 20 25 30
0.00
0.05
0.10
0.15
Days
Main secondaryEPrate UFH
ENOXLog-Rank Test
p=0.01 11.3%
6.7%
30d rate (%)
Death or Complication of MIDeath, resuscitated cardiac arrest, recurrent MI/ACS, Urg Revasc,
stroke, peripheral or pulmonary embolism
0 5 10 15 20 25 30
0.00
0.05
0.10
0.15
Days
DeathorComplication of MI rate
UFHENOX
Log-Rank Test
p=0.02 12.4%
7.8%
30d rate (%)
Death orresuscitated cardiac arrestDeath (any) Death (any)
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
DaysDeathorresuscitatedcardiacarrestrate
UFHENOX Log-Rank Test
p=0.049
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
Days
Deathrate
UFHENOX Log-Rank Test
p=0.08 6.3%
3.8%
30d rate (%)
Main Safety Endpoint Non-CABG Major Bleeding (STEEPLE
definition)
P = NS
% of patients
All Safety Endpoints
% of patients
P = NS for all
Protocole definitions(STEEPLE)
2.4 2.72.92.3
0
2
4
6
8
10
12
14
Death, Complication of MI or Major bleedingNet clinical benefit
15
10,2
0
2
4
6
8
10
12
14
16
UFHENOX
RRR = 32% P = 0.03
% of patients
Enoxaparin vs. unfractionated heparin in patients undergoing primary PCI: Insights from a comprehensive prospective
reperfusion registry of STEMI patients (VITAL HEART RESPONSE)
Welsh, S Sookram, B Tyrrell, S Garg, W Tymchak, B O'Neill, N Brass
Results: in-hospital clinical eventsP=0.03
P=0.02
P=0.05 P=0.04
Composite endpoint: death, re-MI, CHF and major bleeding requiring transfusion
composite endpoint adjusted for: gender, age, height, weight and diabetes
Antiplatelet therapy in STEMI
What antiplatelet strategies have been shown to reduce mortality in STEMI patients?
1. ASA vs. no antiplatelets
2. ASA/clopidogrel vs. ASA
3. ASA/double dose clopidogrel vs ASA/clopidogrel
4. ASA/prasugrel vs. ASA/clopidogrel
5. ASA/ticagrelor vs. ASA/clopidogrel
ISIS-2Reperfusion Synergy
35-day Vascular Mortality
10.7 10.4
8
13.2
0
2
4
6
8
10
12
14
Placebo ASA SK ASA + SKTreatment
% m
orta
lity
ISIS-2. Lancet 1988;2:349
n = 17,187
p < 0.0001ASA vs placeboSK vs placeboCombination vs either
CV Death, MI, RI → Urg Revasc
days
Pe
rce
nta
ge
wit
h e
nd
po
int
(%)
Pe
rce
nta
ge
wit
h e
nd
po
int
(%)
0
5
10
15
0 5 10 15 20 25 30
PlaceboPlacebo
ClopidogrelClopidogrel
Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65(95% CI 0.65--0.97)0.97)
P=0.026P=0.026
20%20%20%
No increase in major bleeding
Days
9% (SE3) relative risk
reduction (2P=0.002)
No increase in major bleeding
Placebo
Clopidogrel
N=45,852N=3491
CV Death, re-MI, Stroke
CLARITY COMMIT
9%9%9%
Clopidogrel and Fibrinolysis
COMMIT: Effect of Clopidogrel on Death in Hospital
Dead(%)
Days since randomisation (up to 28 days)
Placebo + ASA: 1846 deaths (8.1%)
Clopidogrel + ASA:1728 deaths (7.7%)
7% (SE3) relative risk reduction (2P=.03)
Chen Z. Presentation at ACC 2005; Orlando, FL; March 9, 2005
CURRENT Study Design
Clopidogrel High Dose GroupClopidogrel 600mg loading dose Day 1 followed by 150mg from Day 2 to Day 7; 75mg from Day 8 to 30
Clopidogrel Standard Dose GroupClopidogrel 300mg (+placebo) Day 1 followed
by 75mg (+placebo) from Day 2 to Day 7;75mg from Day 8 to 30
RANDOMIZE RANDOMIZE
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
Patients with UA/NSTEMI or STEMI planned for early invasivestrategy, i.e. intend for PCI as early as possible within 72 hrs
RANDOMIZE (n=25,087)
CURRENT – OASIS 7A 2 X 2 factorial randomized trial of optimal clopidogrel and aspirin dosing
in patients with ACS undergoing an early invasive strategy with intent for PCI
Measure Aspirin75–100 mg
Aspirin300–325 mg
Hazard ratio (95% CI)
Cardiovascular death, MI, and stroke (n=25 087)
4.4 4.2 0.96 (0.85–1.08)
•PCI cohort (n=17 232) 4.2 4.1 0.98 (0.84–1.13)•No PCI cohort (n=7855) 4.7 4.4 0.92 (0.75–1.14)
Stent thrombosis 2.1 1.9 0.91 (0.73–1.12)TIMI major bleed 1.03 0.97 0.94 (0.73–1.21)CURRENT major bleed 2.3 2.3 0.99 (0.84–1.17)CURRENT severe bleed 1.7 1.7 1.00 (0.83–1.21)
Results of the aspirin dose comparison: Efficacy and bleeding
CURRENT-OASIS 7 investigators, NEJM, Sept.2, 2010
Measure (n=25 087) Standard clopidogrel
therapy
Double clopidogrel
therapy
Hazard ratio
(95% CI)
Cardiovascular death, MI, and stroke, overall cohort
4.4 4.2 0.94 (0.83–1.06)
CV death 2.2 2.1 0.95 (0.81–1.13)
MI, overall cohort 2.2 1.9 0.86 (0.72–1.02)
Stroke 0.5 0.5 0.99 (0.70-1.40)
Recurrent ischemia 0.4 0.4 0.93 (0.64-1.36)
Double vs standard dose of clopidogrel: Primary outcome and components
CURRENT-OASIS 7 investigators, NEJM, Sept.2, 20
Measure (n=25 087) Standard clopidogrel
therapy
Double clopidogrel
therapy
Hazard ratio
(95% CI)
CURRENT major 2.0 2.5 1.24 (1.05-1.46)
RBC transfusion ≥2 units 1.7 2.2 1.28 (1.07 – 1.54)
CABG related 0.9 1.0 1.09 (0.84-1.40)
Severe 1.6 1.9 1.22 (1.01 – 1.47)
TIMI major 1.3 1.7 1.26 (1.03 – 1.54)
CURRENT Minor 4.3 5.1 1.18 (1.05-1.33)
Double vs standard dose of clopidogrel: Safety outcomes
CURRENT-OASIS 7 investigators, NEJM, Sept.2, 2010
Outcome Standard clopidogrel (n=8684)
Double clopidogrel (n=8548)
Hazard ratio
(95% CI)
CV death, MI, Stroke 4.5 3.9 0.86 (0.74 - 0.99)CV death 1.9 1.9 0.96 (0.77 – 1.19)MI 2.6 2.0 0.79 (0.64 – 0.96)Stroke 0.4 0.4 0.87 (0.53 – 1.41)Definite stent thrombosis 1.2 0.7 0.58 (0.42–0.79)
TIMI major bleeding 0.7 1.0 1.36 (0.97-1.90)CURRENT major bleeding 1.1 1.6 1.41 (1.09–1.83)CURRENT severe bleeding 0.8 1.1 1.34 (0.99–1.82)Fatal bleeding 0.2 0.07 0.46 (0.18–1.22)Red blood cell transfusion ≥2U 0.9 1.3 1.42 (1.06–1.91)CABG-related major bleeding 0.07 0.1 1.70 (0.62–4.69)
Clinical outcomes, stent thrombosis and bleeding events in PCI population
Mehta S. et al, Lancet, sept 1, online, 2010
Inhibition of Platelet Aggregation (Mean ± SEM, 20 µM ADP)
ADP=adenosine diphosphate
Clop=clopidogrelPras=prasugrel
*P<.001 vsClop 300 mg
600 mg and 75 mg
†P <.05 vsClop 300 mg/75
mg
‡P <.001 vsClop 300 mg/75
mg
Inhi
bitio
n of
Plat
elet A
ggre
gatio
n (%
)
0
20
40
60
80
100
Loading Dose Maintenance Doses
2 3 4 5 6 7 8 91 2 3 4 5 6
‡
*
* * * * * * * * * * *
†
†
‡‡
‡
*
DaysTime Day 1, Hours
Clopidogrel
ClopidogrelPrasugrel
10 mg
300 mg
600 mg
75 mg
Jakubowski et al. Cardiovasc Drug Rev. 2007;25:357-374.
60 mg
Clopidogrel Prasugrel
Mechanism of Action Irreversible Irreversible
Dosing route oral oral
Onset of action 3-8 h (prodrug) 1-4 h (prodrug)
Inhibition irreversible irreversible
Maximum Inhibition ~40% Full
Variability +++ ++
Selectivity +++ +++
TRITON TIMI-38 Main Trial Design
Adapted from Wiviott SD, et al. Am Heart J. 2006;152:627-35.
TRITON-TIMI 38: Follow-up Duration for Major Efficacy End Points
ACS=Acute Coronary Syndrome; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; UTVR=Urgent Target Vessel Revascularization
0.5
Prasugrel Better Clopidogrel BetterHR
0.4 0.6 0.7 0.8 0.9 1.1 1.2 1.3 1.41.0 1.5
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
% Risk Reduction P-value
Primary Endpoint 19 <0.001
CV Death 11 0.31
Nonfatal MI 24 <0.001
Nonfatal stroke - 0.93
All Cause Death 5 0.64
CV Death/Nonfatal MI/UTVR 19 <0.001
All Cause Death/Nonfatal MI/Nonfatal Stroke 17 <0.001
UTVR 34 <0.001CV Death/Nonfatal MI/Nonfatal Stroke/Rehospitalization for ischemia 16 <0.001
Stent Thrombosis 52 <0.001
Bleeding Events: Safety Cohort(N=13,457)
Bleeding Events: Safety Cohort(N=13,457)
ARD 0.6%HR 1.32P=0.03
NNH=167
ARD 0.5%HR 1.52P=0.01
ARD 0.2%P=0.23
ARD 0%P=0.74
ARD 0.3%P=0.002
1.8
0.9 0.9
0.1 0.3
2.4
1.41.1
0.4 0.30
2
4
TIMI Major Bleeds
Life Threatening
Nonfatal Fatal ICH
% E
ve
nts
ClopidogrelPrasugrel
ICH in Pts w/ Prior Stroke/TIA
(N=518)
Clop 0 (0) %Pras 6 (2.3)%
(P=0.02)
Patients with STEMI Efficacy of Prasugrel
LD, loading dose; MD, maintenance dose. * Composite primary endpoint of death from CV causes, MI or stroke; † Dotted line represents 30 days.1. Montalescot et al. Lancet. 2009;373:723-31;
TRITON-TIMI 381 Acute ACS patients undergoing planned PCI. Prespecified analysis of STEMI patients
• Prasugrel (60 mg LD, 10 mg/day MD), n=1765• Clopidogrel (300 mg LD, 75 mg/day MD), n=1769
TRITON-TIMI 381 Acute ACS patients undergoing planned PCI. Prespecified analysis of STEMI patients
• Prasugrel (60 mg LD, 10 mg/day MD), n=1765• Clopidogrel (300 mg LD, 75 mg/day MD), n=1769
Primary Endpoint*
Hazard Ration – 30 Days0.68 (95% CI 0.54-0.87)
p=0.0017
Hazard Ration – 30 Days0.68 (95% CI 0.54-0.87)
p=0.0017
Hazard Ratio – 15 Months0.79 (95% CI 0.65-0.97)
p=0.0221
Hazard Ratio – 15 Months0.79 (95% CI 0.65-0.97)
p=0.0221
Number at riskClopidogrel 1765 1543 1522 1506 1492 1481 1465 1459 1436 1177
Prasugrel 1769 1588 1570 1551 1535 1517 1502 1493 1475 1226
Safety of Prasugrel vs. ClopidogrelPatients with STEMI
TIMI Major Bleeding Unrelated to CABG
TIMI major bleeding unrelated to CABG was similar in clopidogrel and prasugrel
groups at 30 days and 15 months. In patients who underwent CABG (<4%)
prasugrel was associated with significantly increased risk of TIMI major
bleeding after CABG at 15 months, compared to clopidogrel.
TIMI major bleeding unrelated to CABG was similar in clopidogrel and prasugrel
groups at 30 days and 15 months. In patients who underwent CABG (<4%)
prasugrel was associated with significantly increased risk of TIMI major
bleeding after CABG at 15 months, compared to clopidogrel.
†
† Dotted line represents 30 days.1. Montalescot et al. Lancet. 2009;373:723-31.
Number at riskidogrel 1740 1584 1533 1502 1469 1440 1410 1390 1357 1110 rasugrel 1736 1551 1523 1503 1475 1449 1415 1400 1354 1092
Ticagrelor and clopidogrel: Metabolism
CYP-dependentoxidationCYP1A2CYP2B6CYP2C19
CYP-dependentoxidationCYP2C19 CYP3A4/5 CYP2B6
Active compound
Active metabolite
Intermediate metabolite
Prodrug
Ticagrelor
Clopidogrel
Binding
ADP P2Y12 recept
or
Platelet
Ticagrelor:Orally active; does not require metabolic activation1
Ticagrelor:Orally active; does not require metabolic activation1
Clopidogrel:A produg; requires hydrolysis by esterase followed by
CYP-dependent oxidation to generate active compound.2
Clopidogrel:A produg; requires hydrolysis by esterase followed by
CYP-dependent oxidation to generate active compound.2
CYP-dependentoxidationCYP3A4/5
Ticagrelor has a faster rate of offset of IPA as compared to clopidogrel in patients with stable CAD
IPA is similar between ticagrelor (58%) and
clopidogrel (52%)
Ticagrelor
PLATO Study Design
Primary endpoint: • CV death + MI + Stroke Key secondary: • CV death + MI + Stroke in patients intended for invasive management
• Total mortality + MI + Stroke • CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events
• MI alone / CV death alone / Stroke alone / Total mortalityPrimary safety: • Total major bleeding
6–12 month exposure
ClopidogrelIf pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor180 mg loading dose, then90 mg bid maintenance;
(additional 90 mg pre-PCI)
UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI)All receiving ASA; clopidogrel-treated or naive;
randomised within 24 hours of index event (N=18,624)
UA = unstable angina; PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
James S, et al. Am Heart J. 2009;157:599-605.
PLATO Hierarchical Testing of Major Efficacy EndpointsPLATO Hierarchical Testing of Major Efficacy Endpoints
All Patients*All Patients*Ticagrelor Ticagrelor (n=9,333)(n=9,333)
Clopidogrel Clopidogrel (n=9,291)(n=9,291)
HR for HR for ticagrelor (95% ticagrelor (95%
CI)CI) PP valuevalue✝✝
Primary Objective,n (%/yr)
CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77-0.92) <0.001
Secondary Objectives, n Secondary Objectives, n (%/yr)(%/yr)
Total death + MI + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77-0.92) <0.001CV death + MI + stroke +
severe + recurrent ischemia + TIA + arterial thrombus
1,290 (14.6) 1,456 (16.7) 0.88 (0.81-0.95) <0.001
MI 504 (5.8) 593 (6.9) 0.84 (0.75-0.95) 0.005CV death 353 (4.0) 442 (5.1) 0.79 (0.69-0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91-1.52) 0.22
Total Death 399 (4.5) 506 (5.9) 0.78 (0.69-0.89) <0.001
*The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category.
✝By Cox regression analysis using treatment as factor.
Wallentin L, et al.New Engl J Med. 2009;361.CV=cardiovascular; MI=myocardial infarction; yr=year; HR=hazard ratio; CI=confidence intervals; K-M=Kaplan-Meier; TIA=transient ischemic attack
PLATO NonPLATO Non--CABG and CABG and CABGCABG--related Major Bleedingrelated Major Bleeding
NS = not significant; K-M=Kaplan-Meier; CABG=coronary-artery bypass grafting
Wallentin L, et al.New Engl J Med. 2009;361.
p=0.03
p=0.03
NS
NS
K-M
est
ima
ted
ra
te (
% p
er
yea
r)
Non-CABGPLATO major
bleeding
8
7
6
5
4
3
2
1
0Non-CABGTIMI major
bleeding
CABGPLATO major
bleeding
CABG TIMI major
bleeding
TicagrelorClopidogrel
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
For patients requiring CABG ‘recommended that the study drug be withheld — clopidogrel group, for 5 days, and in the ticagrelor
group, for 24 to 72 hours
Patients with STEMI Efficacy of Ticagrelor
LD, loading dose; MD, maintenance dose. * Composite primary endpoint of death from CV causes, MI or stroke; † Dotted line represents 30 days.. Steg et al. Circulation. 2010;122:2131-41.
PLATO2 Acute ACS patientsSubgroup analysis of STEMI patients
• Ticagrelor (180 mg LD, 10 mg/day MD BID), n=3752• Clopidogrel (300 mg LD, 75 mg/day MD), n=3792
PLATO2 Acute ACS patientsSubgroup analysis of STEMI patients
• Ticagrelor (180 mg LD, 10 mg/day MD BID), n=3752• Clopidogrel (300 mg LD, 75 mg/day MD), n=3792
Hazard Ratio0.87 (95% CI 0.75-1.01)
p=0.07
Hazard Ratio0.87 (95% CI 0.75-1.01)
p=0.07
Primary Endpoint*
Number at riskClopidogrel 3792 3501 3438 3356 2726 2097 1679
Ticagrelor 3752 3476 3424 3331 2687 2049 1675
Safety of Ticagrelor vs. ClopidogrelPatients with STEMI
*TIMI bleeding rates were calculated, not adjudicated; †Primary safety endpoint,.1. Steg et al. Circulation. 2010;122:2131-41.
Major bleeding† and TIMI bleeding were similar in the clopidogrel and ticagrelor
groups.
Major bleeding† and TIMI bleeding were similar in the clopidogrel and ticagrelor
groups.
Vital Heart ResponseRegional reperfusion protocol
• Pharmacological reperfusion
• ASA, clopidogrel, enoxaparin and TNK
• Adjusted for age >75 (clopid and enox)
• Mechanical reperfusion
• Ambulance protocol
• ASA, clopidogrel (600 mg), enoxaparin (IV 30 mg & SQ 1 mg/kg)
• GP IIb/IIIa in cath lab
• In-hospital protocol
• ASA, clopidogrel (300-600 mg), UFH 70 U/kg/bivalirudin/enoxaparin
• GP IIb/IIIa in cath lab
. Canadian Cardiovascular Society Working Group: Providing a perspective on the 2007 focused update of the American College of Cardiology and
American Heart Association 2004 guidelines for the management ofST elevation myocardial infarction.
• with the exception of aspirin, both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs have been associated with increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture3.
• Therefore, patients that present with STEMI who are routinely taking nonsteroidal anti-inflammatory agents should have these drugs discontinued immediately and for those requiring ongoing therapy for pain aspirin and/or morphine sulfate are appropriate alternatives.
Welsh et al, Can J Cardiol. 2009 Jan;25(1):25-32.
• Early aggressive beta blocker therapy (intravenous and oral) was not associated with clinical benefit but was actually associated with increased risk when delivered to a broad spectrum of STEMI patients within the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT II)4.
• Evidence still supports the administration of oral beta blocker therapies initiated within the first 24 hours in patients who do not have signs of heart failure, low output states, increased risk for cardiogenic shock, or other relative contraindications for beta blockers (first, second, or third degree heart block, active asthma, or reactive airway disease).
Welsh et al, Can J Cardiol. 2009 Jan;25(1):25-32.
. Canadian Cardiovascular Society Working Group: Providing a perspective on the 2007 focused update of the American College of Cardiology and
American Heart Association 2004 guidelines for the management ofST elevation myocardial infarction.
• Beta blockers should be initiated at low to moderate doses and titrated consistent with patient stability, heart rate and blood pressure response. Intravenous beta-blockers maintain clinical utility in selected patient populations, especially those with ongoing myocardial ischemia associated with significant hypertension and in the absence of high-risk features for congestive heart failure or cardiogenic shock.
Welsh et al, Can J Cardiol. 2009 Jan;25(1):25-32.
. Canadian Cardiovascular Society Working Group: Providing a perspective on the 2007 focused update of the American College of Cardiology and
American Heart Association 2004 guidelines for the management ofST elevation myocardial infarction.
STEMI Oct. 31, 2011 Core Curriculum
Adjunctive/Conjunctive pharmacological therapy
Robert C. Welsh, MD, FRCPCAssociate Professor, University of Alberta
Director, Adult Cardiac Catheterization and Interventional CardiologyCo-Director, University of Alberta Chest Pain Program
Co-Chair, Vital Heart Response
