Pharmacologic Options in
the Invasive Management
of Acute Coronary
Syndrome
Ross J. Goodfellow, DO FACC FSCAI
Health First Medical Group
Cape Canaveral Hospital/Holmes Regional Medical Center
Cocoa Beach & Melbourne, Florida
Disclosures
• Speaker
• Astra Zeneca
• Zoll Medical
Acute Coronary Syndrome
(UA, NSTEMI, STEMI)
•
2014
•
•
Majority of patients undergo invasive
strategy (cardiac cath within 24-48 hrs)
FRISC-II, RITA, ICTUS
•
Meta-analysis demonstrated 19% RRR
in CV Death or MI in patients managed
with early invasive strategy
Risk Stratification:
TIMI Risk Score
• Age 65 or older
• 3 or more CAD risk factors
• DM, Smoking, HTN, HDL<40mg/dl, FamHx of premature
CAD
• Known CAD
• ASA use in past 7 days
• 2 or more anginal episodes in 24 hours
• ST changes > 0.5mV
• Positive cardiac biomarkers
ACS Pharmacology:
Invasive Strategy
• Decrease myocardial demand/increase supply
• Beta Blockers, Nitrates, Calcium Channel Blockers
• Analgesics
• Morphine
• Oral Antiplatelet Agents
• ASA, Clopidogrel, Prasugrel, Ticagrelor
• Intravenous Antiplatelet Agents
• IIb/IIIa Antagonists (Abciximab, Eptifibitide, Tirofiban)
• Anticoagulants
• Heparin, Bivalirudin, LMWH (Enoxaparin, Dalteparin)
Sites of action of antiplatelet and anticoagulant
medications1
ANGIOMAX
Platelet activation
GP IIb/IIIa inhibitors
Heparin
LMWH
AT
Thrombin
AT
Factor
Xa
Aspirin and
Thienopyridines
ADP/TXA2
mediated
platelet
adhesion
Fibrinogen
Prothrombin
Plasma clotting factors
Collagen
1. Monroe DM et al. Arterioscler Thromb Vasc Biol 2002;22:1381-9
Tissue factor
Platelet aggregation
Fibrin
Vessel Injury
8
Enoxaparin v. UFH
• Meta-analysis of all trials demonstrates a
10% reduction in death or MI with
enoxaparin over UFH
• No significant differences in major
bleedings
• Meta-analysis included conservatively
managed patients
• Largest trial of invasively treated patients
(SYNERGY) showed increased bleeding
with enoxaparin
Oral Antiplatelet Agents
• ADP-P2Y12 interaction
• Amplifies platelet activation
• P2Y12 receptor antagonists
• Thienopyridines
• Ticlopidine
• Clopidogrel (PLAVIX)
• Prasugrel (EFFIENT)
• CPTP (Cyclopentyltriazolopyrimidine)
• Ticagrelor (BRILINTA)
CURE Trial
• Unstable angina/NSTEMI
• ASA + Clopidogrel (300mg load/75mgqd) v.
ASA alone
• N=12,562
• 20% RRR in CV Death, MI, and Stroke in
Clopidogrel group
• Driven by decreased nonfatal MI
• PCI-CURE
• Clopidogrel pre-treatment (6 days) pre-PCI
associated with 31% RRR in primary endpoint
PCI-CURE
CURRENT-OASIS 7
• Rationale
• Attempt to address high on-treatment
platelet reactivity seen in 10-30% pts.
• Double-dose clopidogrel
load/maintenance dose x 7 days v.
standard dose in ACS pts.
• 2 x 2 design also assessing ASA dose
Wiviott SD et al AHJ 152: 627,2006
Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
N= 13,600
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint: CV death, MI, Stroke
2o endpoints:
CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Enrollment Criteria
•Inclusion Criteria
Planned PCI for :
Known
Mod-High Risk UA/NSTEMI (TRS > 3)
Anatomy
STEMI: < 14 days (ischemia or Rx strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
–Severe comorbidity
–Increased bleeding risk
–Prior hemorrhagic stroke or any stroke < 3 mos
–Any thienopyridine within 5 days
–No exclusion for advanced age or renal function
Wiviott SD et al AHJ 152: 627,2006
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
12.1
(781)
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
NNT= 46
LTFU = 14 (0.1%)
ITT= 13,608
0
0 30 60 90
Wiviott SD et al NEJM 357: 2001, 2007
180
Days
270
360
450
Components of Endpoints
Clopidogrel
Prasugrel
HR
12.1
9.9
0.81
CV Death
2.4
2.1
0.89
Nonfatal MI
9.5
7.3
0.76
1.0
1.0
1.02
CV Death, MI, Stroke
Nonfatal Stroke
3.2
0.95
3.0
All Cause Mortality
uTVR
Stent
Thrombosis
0.5
Prasugrel Better
1
HR
3.7
2.5
0.66
2.4
1.1
0.48
Clopidogrel Better
2
Wiviott SD et al NEJM 357: 2001, 2007
Balance of
Efficacy and Safety
138
events
15
Clopidogrel
12.1
Endpoint (%)
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46
Prasugrel
5
TIMI Major
NonCABG Bleeds
Prasugrel
35
events
2.4
1.8
Clopidogrel
0
0
30 60 90
180
Days
270
360
450
HR 1.32
(1.03-1.68)
P=0.03
NNH = 167
Wiviott SD et al NEJM 357: 2001, 2007
Bleeding Events
Safety Cohort
(N=13,457)
3.0
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
2.4
Prasugrel
2.3
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
1.8
1.4
1.5
0.9
0.9
1.1
0.8
0.0
0.4
0.1
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
0.3
0.3
ICH
ARD 0.3%
P=0.002
ARD 0%
P=0.74
Wiviott SD et al NEJM 357: 2001, 2007
Net Clinical Benefit
Death, MI, Stroke,
Major Bleed (non CABG)
15
Clopidogrel
ITT= 13,608
13.9
Endpoint (%)
12.2
Prasugrel
10
HR 0.87
P=0.004
Events per 1000 pts
+
9
6
All Cause
Mortality
0
5
-9
-19
-28
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
180
Days
270
360
Clop 3.2%
Pras 3.0 %
P=0.64
450
Wiviott SD et al NEJM 357: 2001, 2007
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
0.5
Pinter = NS
19
OVERALL
Prasugrel Better
1
HR
Clopidogrel Better
2
Wiviott SD et al NEJM 357: 2001, 2007
Net Clinical Benefit
Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
+ 54
Yes
Pint = 0.006
No
-1
>=75
Age
Pint = 0.18
< 75
Wgt
-16
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
Wiviott SD et al NEJM 357: 2001, 2007
August 30, 2009 at 08.00 CET
Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
HO
N
N
N
H
N
HO
O
F
N
N
S
Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP)
F
OH
•
–
–
–
•
–
–
–
Direct acting
Not a prodrug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor
Greater inhibition of platelet aggregation than clopidogrel
Reversibly bound
Degree of inhibition reflects plasma concentration
Faster offset of effect than clopidogrel
Functional recovery of all circulating platelets
PLATO study design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack
Cumulative incidence (%)
K-M estimate of time to first primary efficacy
event (composite of CV death, MI or stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
11.7
Clopidogrel
9.8
Ticagrelor
HR 0.84 (95% CI 0.77–0.92), p=0.0003
0
60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,743
5,096
4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Hierarchical testing major efficacy endpoints
All patients*
Primary objective, n (%)
CV death + MI + stroke
Secondary objectives, n (%)
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
CV death
Stroke
Total death
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for
(95% CI)
864 (9.8)
1,014 (11.7) 0.84 (0.77–0.92)
<0.001
901 (10.2)
1,065 (12.3) 0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95)
<0.001
504 (5.8)
353 (4.0)
125 (1.5)
593 (6.9)
442 (5.1)
106 (1.3)
0.84 (0.75–0.95)
0.79 (0.69–0.91)
1.17 (0.91–1.52)
0.005
0.001
0.22
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.
p value†
Secondary efficacy endpoints over time
Cardiovascular death
Myocardial infarction
7
Clopidogrel
6
6
5.8
5
Ticagrelor
4
3
2
1
HR 0.84 (95% CI 0.75–0.95), p=0.005
0
0
60
120
180
240
300
360
Cumulative incidence (%)
Cumulative incidence (%)
7
6.9
Clopidogrel
5
4.0
4
Ticagrelor
3
2
1
HR 0.79 (95% CI 0.69–0.91), p=0.001
0
0
60
120
180
240
300
360
Days after randomisation
Days after randomisation
No. at risk
5.1
Ticagrelor
9,333
8,678
8,520
8,279
6,796
5,210
4,191
9,333
8,294
8,822
8,626
7119
5,482
4,419
Clopidogrel
9,291
8,560
8,405
8,177
6,703
5,136
4,109
9,291
8,865
8,780
8,589
7079
5,441
4,364
Stent thrombosis
(evaluated in patients with any stent during the study)
Ticagrelor
(n=5,640)
Clopidogrel HR
(n=5,649)
(95% CI)
p value
106 (1.9)
0.009
Stent thrombosis, n (%)
Definite
71 (1.3)
Probable or definite
118 (2.1)
Possible, probable, definite
155 (2.8)
0.67 (0.50–0.91)
158 (2.8)
0.75 (0.59–0.95) 0.02
202 (3.6)
0.77 (0.62–0.95) 0.01
*Time-at-risk is calculated from first stent insertion in the study or date of randomisation
Time to major bleeding – primary safety event
K-M estimated rate (% per year)
15
Ticagrelor
10
Clopidogrel
11.58
11.20
5
HR 1.04 (95% CI 0.95–1.13), p=0.434
0
0
60
120
180
240
300
360
Days from first IP dose
No. at risk
Ticagrelor
9,235
7,246
6,826
6,545
5,129
3,783
3,433
Clopidogrel
9,186
7,305
6,930
6,670
5,209
3,841
3,479
Total major bleeding
13
12
NS
11.6
Ticagrelor
Clopidogrel
11.2
K-M estimated rate (% per year)
11
NS
10
8.9
NS
9
7.9
8
8.9
7.7
NS
7
5.8
6
5.8
5
4
3
2
NS
1
0.3
0.3
0
PLATO major
bleeding
TIMI major
bleeding
Red cell
transfusion*
PLATO lifethreatening/
fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use
of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;
*Proportion of patients (%); NS = not significant
Non-CABG and CABG-related major bleeding
9
7.9
8
K-M estimated rate (% per year)
Ticagrelor
Clopidogrel
NS
7.4
7
NS
5.8
6
5.3
p=0.026
5
4
4.5
3.8
p=0.025
2.8
3
2.2
2
1
0
Non-CABG
PLATO major
bleeding
Non-CABG
TIMI major bleeding
CABG
PLATO major
bleeding
CABG
TIMI major bleeding
Holter monitoring & Bradycardia related events
Holter monitoring at first week
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
Holter monitoring at 30 days
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
Bradycardia-related event, %
Ticagrelor
(n=1,451)
5.8
2.0
Ticagrelor
(n= 985)
2.1
Clopidogrel
(n=1,415)
3.6
1.2
Clopidogrel
(n=1,006)
1.7
0.8
0.6
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
p value
0.01
0.10
p value
0.52
0.60
Pacemaker Insertion
0.9
0.9
p value
0.87
Syncope
1.1
0.8
0.08
Bradycardia
4.4
4.0
0.21
Heart block
0.7
0.7
1.00
Other findings
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
p value*
Any
13.8
7.8
<0.001
With discontinuation of study treatment
0.9
0.1
<0.001
Any
1.4
1.7
0.17
Malignant
1.2
1.3
0.69
Benign
0.2
0.4
0.02
All patients
Dyspnoea, %
Neoplasms arising during treatment, %
*p values were calculated using Fischer’s exact test
Conclusions
• Reversible, more intense P2Y12 receptor inhibition for one year
with ticagrelor in comparison with clopidogrel in a broad
population with ST- and non-ST-elevation ACS provides
– Reduction in myocardial infarction and stent thrombosis
– Reduction in cardiovascular and total mortality
– No change in the overall risk of major bleeding
Ticagrelor is a more effective alternative than clopidogrel
for the continuous prevention of ischaemic events, stent
thrombosis and death in the acute and long-term treatment
of patients with ACS
IIb/IIIa Antagonists
• Inhibit >80% of platelet aggregration
• Early studies demonstrated short and long term
event reduction in ACS patients compared with
heparin alone
• Driven by reduction in peri-procedural MI
• Increased bleeding
• Recent Trials
• ISAR-REACT 2, EARLY ACS, ACUITY
ACUITY Study Design – First Randomization
UFH/Enox
+ GP IIb/IIIa
(n=4,603)
Moderateand highRisk ACS
(n=13,819)
Aspirin in all
clopidogrel;
dosing and timing
per local practice
R*
Bivalirudin
+ GP IIb/IIIa
(n=4,604)
Bivalirudin
Alone†
(n=4,612)
Angiography within 72h
Moderate- and high-risk unstable angina or NSTEMI
undergoing an early invasive strategy (N=13,819)
Medical
management
PCI
CABG
*Stratified by pre-angiography thienopyridine use or administration
†ANGIOMAX alone (with GP IIb/IIIa inhibition reserved for severe breakthrough ischemia and procedural complications during PCI)
The safety and effectiveness of ANGIOMAX have not been established in patients with acute coronary syndromes (ACS) who are
not undergoing PTCA or PCI.
Stone GW et al. N Engl J Med. 2006;355:2203-2216
47
11
Overall ACUITY Management
Strategy (N=13,819)
Medical Rx (n=4,491)
CABG (n=1,539)
11.1%
32.5%
56.4%
PCI (n=7,789)
UFH/Enox +
GP IIb/IIIa
N = 2,561
48
12
Stone GW et al. N Engl J Med. 2006;355:2203-2216
Bivalirudin +
GP IIb/IIIa
N = 2,609
Bivalirudin alone
N = 2,619
Primary Results – 30 Days
UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone
UFH/Enox+GP IIb/IIIa (N=2561)
Bivalirudin+GP IIb/IIIa (N=2609)
Bivalirudin alone (N=2619)
30 day events (%)
20%
P=.10
13%
P=.057
15%
P=.16
P=.45
P=.32
P<.001
12%
8%
9%
9%
7%
8%
4%
0%
Net clinical outcome
49
16
Composite ischemia Major bleeding (non-CABG)
Stone GW et al. Lancet. 2007;369:907-919.
Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information
Early and Late Mortality
UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone
4.0
30-day
Estimate
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone
Mortality (%)
3.0
0.9%
1.2%
1.1%
P
(log rank)
—
0.45
0.63
1-year
Estimate
P
(log rank)
3.1%
2.4%
2.2%
—
0.70
0.48
p=0.78
2.0
1.0
0.0
0
31
62
92
123 154 185 215 246 277 308 338 369 400
Days from Randomization
Data on file, The Medicines Company, Parsippany, NJ.
Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information
50
19
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG
– Primary PCI
3006 pts eligible for stent randomization
Paclitaxel-eluting TAXUS stent
– Medical Rx
R
3:1
Bare metal EXPRESS stent
Clinical FU at 30 days, 6 months, 1 year, and then
yearly through 3 years; angio FU at 13 months
Stone, GW N Engl J Med 2008;358:2218-30.
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI
R
1:1
Randomized
UFH + GP IIb/IIIa
N=1802
28
1-Year FU Eligible
1-Year FU
3-Year FU
Bivalirudin
N=1800
• • • Not true MI* • • •
N=1774
29
N=1771
26
• • • Withdrew • • •
22
46
• • • Lost to FU • • •
53
N=1702
N=1696
17
• • • Withdrew • • •
18
57
• • • Lost to FU • • •
44
N=1628
N=1634
* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-Year Major Bleeding
(non-CABG)*
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
12
10.5%
Major Bleeding (%)
10
9.4%
8
6.9%
6
6.0%
3-yr HR (95%CI)
4
0.64 (0.51, 0.80)
P=0.0001
2
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
* Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL
with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Time in Months
'
Time in Months
3-Year Cardiac Mortality
Heparin + GPIIb/IIIa (n=1802)
3-yr HR (95%CI)
0.56 (0.40, 0.80)
P=0.001
6
5
Cardiac Mortality (%)
Bivalirudin alone (n=1800)
5.1%
4
3.8%
2.9%
3
2
2.1%
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
3-Year Reinfarction
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
10
9
8.2%
Reinfarction (%)
8
7
6.2%
6
5
4.4%
4
3
3-yr HR (95%CI)
0.76 (0.59, 0.99)
P=0.04
3.6%
2
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
Conclusions:
Pharmacology Randomization
● In this large-scale, prospective, randomized trial of pts with STEMI
undergoing primary PCI, the initial treatment with bivalirudin alone
compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted
in:
– A significant 36% reduction in major bleeding and a significant
24% reduction in reinfarction, with non significantly different rates
of stent thrombosis, TVR and stroke
– A significant 44% reduction in cardiac mortality and a 25%
reduction in all-cause mortality, the latter representing 18 lives
saved per 1000 patients treated with bivalirudin (NNT = 54 to
save 1 life)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Other Issues to
Consider...
•
•
Timing of intervention
•
Emergent v. Urgent (24-48 hours)
Access site
•
•
•
Femoral, Radial, Brachial
Closure device
Maintaining access vessel patency
(upper extremity)
My preferences
• Emergency PCI (STEMI, Unstable NSTEMI)
• Patient on antiplatelet therapy
• Bivalirudin (or UFH)
• Reload in ED (Ticagrelor 180mg)
• IIb/IIIa antag as “bailout”
• Patient antiplatelet naive
• Bivalirudin/UFH
• Lower threshold to use IIb/IIIa antagonist
• Oral antiplatelet on table (Ticagrelor)
My preferences (Cont’d)
• Delayed angiography/PCI
• Bivalirudin/UFH
• IIb/IIIa antagonists if markedly rising
enzymes
• Ticagrelor, Clopidogrel
The Future...
• CANGRELOR
• BRIDGE Trial
• Cangrelor “bridging” decreased platelet reactivity in patients with
prior stents scheduled for CABG
• CHAMPION-PHOENIX Trial
• Cangrelor v. Clopidogrel in PCI patients
• Early results show decreased ischemic events at 48 hours in
cangrelor group v. clopidogrel
• Platelet function assays to guide antiplatelet Rx
• Pharmacogenomic Studies, etc.
QUESTIONS?
THE END