Disclosures
All relevant financial relationships with commercial interests
reported by faculty speakers, steering committee members,
non-faculty content contributors and/or reviewers, or their
spouses/partners have been listed in your program syllabus.
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and Drug
Administration. PCME does not recommend the use of any agent outside of
the labeled indications. Please refer to the official prescribing information for
each product for discussion of approved indications, contraindications and
warnings. The opinions expressed are those of the presenters and are not to
be construed as those of the publisher or grantors.
Pre-activity Medical Knowledge Questions
• Please take out the Pre-activity Survey from the
front of your packet
• Your answers are important to us and will be used
to help shape future CME activities
Polling Question
Pre-activity Survey
How confident are you in your ability to adopt evidencebased use of antiplatelet therapy in the long-term
management of ACS patients?
1
Not at all confident
2
3
4
5
Expert
Polling Question
Pre-activity Survey
Following a myocardial infarction, risk of ischemic events is
increased for:
A. the following month
B. up to 6 months
C. up to a year
D. longer than a year
E. there are insufficient data to draw conclusions
Polling Question
Pre-activity Survey
Results from multiple clinical trials indicate that P2Y12
antagonists reduce the absolute number of ischemic events:
A. equally for high-risk and low-risk patients
B. more for high-risk patients than low-risk patients
C. more for low-risk patients than high-risk patients
D. there are insufficient clinical data to determine
Polling Question
Pre-activity Survey
In the initial medical management of patients with ACS, how
long do current professional society guidelines recommend
the use of dual antiplatelet therapy?
A. 30 days
B. 3 months
C. 6 months
D. 12 months
E. Indefinitely
Polling Question
Pre-activity Survey
Longer-term (>1 year) dual antiplatelet therapy (ASA +
P2Y12 inhibitor or PAR-1 inhibitor) results in reduction of
recurrent ischemic events and:
A. reduced bleeding risk
B. unchanged bleeding risk
C. transient (6-month) increased bleeding risk
D. sustained increased bleeding risk
Polling Question
Pre-activity Survey
Protease-activated receptor 1 (PAR-1) direct thrombin
inhibition describes the mechanism of antithrombotic action
of:
A. clopidogrel
B. prasugrel
C. rivaroxaban
D. ticagrelor
E. vorapaxar
Learning Objectives
At the conclusion of this activity, participants should be able
to demonstrate the ability to:
• Appraise the clinical data supporting long-term use of
antithrombotics in patients with a history of CVD
• Analyze processes of switching therapies or employing
concomitant therapies to achieve optimal balance of antiischemic protection vs bleeding risk
• Customize longer-term therapies to the needs of particular
patients, taking into consideration the evolving landscape
of additional indications
Clinical Impact of Recurrent
CVD; Therapeutic
Opportunities
Patients with Prior MI Remain at High Risk
for Ischemic Events
REACH Registry (4-year outcomes)
64,977 patients ≥45 years old
CV Death, MI, Stroke
24
21.1
20
17.2
16
8
12.2
Percent
12
9.1
4
0
Prior Ischemic Event <=1 Yr
Bhatt DL et al. JAMA. 2010;304:1350-1357.
Prior Ischemic Event >1y
Stable Atherosclerotic disease
Rick Factor only
Secondary Prevention
Patients with History of Atherothrombosis
• Stable outpatients with a history of atherothrombosis remain
at a heightened risk of ischemic events for the long term
• Fundamental aspects of secondary prevention include:
– Lifestyle interventions, including management of risk factors
– Antithrombotic therapies
•
who to treat?
•
which agents to use?
•
how long to treat?
2º PREVENTION:
Lifestyle Changes
Lifestyle/Risk Factor Goals
Risk Factor
Goal
Smoking
Diet
Total Dietary Fat / Saturated Fat
Fish/Omega 3
Dietary Cholesterol
Dietary Sodium
Physical Activity
Cessation
Weight Loss / Maintenance
BMI (Plus Waist Circumference)
Initial BMI
Weight Loss Goal
25-27.5
BMI <25 (WC <40in/35)
>27.5
10% relative weight loss
<140/90 mmHg
Intensive statin therapy
>40 mg/dL for men; >50 mg/dL women
<130 mg/dL(<100 IIa) if TG ≥200 mg/dL
HbA1c <7.0%
Blood Pressure
LDL Cholesterol (primary goal)
HDL Cholesterol
Non-HDL Cholesterol (secondary goal)
Diabetes
Smith SC et al. J Am Coll Cardiol. 2011;58:2432-2446.
<30% calories / <7% calories
≥3 servings/week; 1 g/day
<200 mg/day
<2,000 mg/day (DASH diet goal)
>30 min/day; 5 times/week (daily IIa)
Stone JN et al. J Am Coll Cardiol. 2014;63:2889-2934.
Lifestyle Interventions and Outcomes
Meta-analysis of 9 RCTs evaluating patient-tailored multifactorial
lifestyle interventions aimed at reducing more than one
cardiovascular risk factor in patients with established CHD
Fatal CV events reduced by 18% overall
de Waure C et al. Am J Prev Med. 2013;45:207-216.
2º Prevention: Antithrombotic Therapies
Thromboxane-A2 inhibition
P2Y12 antagonism
PAR-1 antagonism
Factor Xa inhibition
Atherothrombosis:
Clinical Manifestations
Acute Coronary Syndromes
– STEMI
– NSTEMI
– Unstable angina
Stable CAD
Atrial Fibrillation
Angioplasty
Bare metal stent
Drug eluting stent
CABG
Abdominal Aortic Aneurysm
(AAA)
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Stroke
TIA
Intracranial stenosis
Carotid artery stenosis
CEA
Carotid stenting
Renal artery stenosis
Renal artery stenting
Peripheral Arterial Disease
Acute Limb Ischemia
Claudication
Amputation
Endovascular stenting
Peripheral bypass
Abnormal ABI
Plaque Rupture
Aspirin
Collagen/vWF
ACS/PCI
Prothrombin
TF + FVIIa
P2Y12
Rivaroxaban
Apixaban
Edoxaban
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
TxA2
Factor
Xa
Amplification
Vorapaxar
Fondaparinux
LMWH
UFH
ADP
Granule
Secretion
ATIII
GPIIb/IIIa
Activation
Thrombin
Bivalirudin
Dabigatran
Abciximab
Eptifibatide
Tirofiban
Fibrinogen
Curzen N et al. Lancet 2013;382:633–643.
Fibrin
+
Platelet
Aggregation
Platelet-Fibrin
Clot
Ischemic
Events
Antiplatelet Agents
PAR-1 Antagonists:
Atopaxar
Vorapaxar
Desai NR, Bhatt DL. JACC Cardiovasc Interv. 2010;3:571-583.
Bhatt DL et al. Circ Res. 2014;114:1929-1943.
In: Fuster V, Kovacic J. Compendium on ACS.
2º PREVENTION:
Antithrombotic Therapies
Thromboxane-2 inhibition – Aspirin
Aspirin Evidence: Secondary Prevention
Effect of Antiplatelet Treatment* on Vascular Events**
Category
Acute MI
Acute CVA
Prior MI
Prior CVA/TIA
Other high risk
CVD
(e.g. unstable angina, heart failure)
PAD
(e.g. intermittent claudication)
High risk of embolism (e.g. Afib)
Other (e.g. DM)
All trials
% Odds Reduction
0.0
*Aspirin was the predominant antiplatelet agent studied
**Include MI, stroke, or death
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.
0.5
1.0
Antiplatelet better
1.5
2.0
Control better
CURRENT-OASIS 7
Aspirin Results
Patients with UA/NSTEMI/STEMI planned for early invasive strategy
(i.e. intended for PCI as early as possible within 72 hours)
Randomized
ASA Low-dose Group
ASA High-dose Group
At least 300 mg LD day 1; 75-100 mg from
days 2 to 30
At least 300 mg LD day 1; 300-325 mg from
days 2 to 30
Measure
Low Dose (%)
High Dose (%)
HR (95% CI)
P Value
Overall (n = 25,086)
4.4
4.2
0.97 (0.86-1.09)
0.61
PCI cohort (n = 17,263)
4.2
4.1
0.98 (0.84-1.13)
0.76
Stent Thrombosis
2.0
1.9
0.91 (0.73-1.12)
0.37
TIMI Major Bleed
1.4
1.6
1.09 (0.89-1.34)
0.39
CV death/MI/Stroke
CI = confidence interval; CV = cardiovascular; HR = hazard ratio; MI = myocardial infarction; TIMI = thrombolysis in myocardial infarction.
Mehta SR et al. N Engl J Med. 2010;363:930-942.
Mehta SR et al. Lancet. 2010;376:1233-1243.
Mehta SR et al. CURRENT-OASIS 7 presentation. Available at: www.clinicaltrialresults.org. Accessed: February 16, 2012.
2º PREVENTION:
Antithrombotic Therapies
P2Y12 Inhibition – Clopidogrel
CAPRIE:
Superior Efficacy of Clopidogrel versus Aspirin
Cumulative event rate* (%)
20
Patients with recent ischemic stroke, recent MI, or symptomatic
peripheral artery disease
Aspirin
8.7%† RRR
(P=0.043)
Clopidogrel
16
12
8
4
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Months of follow-up
*MI, ischemic stroke, or vascular death
†Intent-to-treat analysis (n=19,185)
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
CAPRIE: Clopidogrel Provides Amplified
Benefit in Patients with High Vascular Risk
RRR 14.9%
P=0.045
Event rate/year* (%)
12
10
RRR 8.7%
P=0.043
10.2%
8.8%
8
6
5.8%
ASA
Clopidogrel
5.3%
4
2
0
All CAPRIE
patients
(n=19,099)
CAPRIE patients with
history of major acute
event: MI or stroke
(n=4496)
*MI, ischemic stroke, or vascular death; mean duration of treatment was 1.6 years
Ringleb PA et al. Stroke. 2004;35:528-532.
CURE Study
Primary End Point: MI/Stroke/CV Death
Cumulative Hazard Rate
0.14
20%
Relative
Risk
Reduction
Placebo
+ Aspirin
(n=6,303)
0.12
0.10
0.08
Clopidogrel
+ Aspirin
(n=6,259)
0.06
0.04
P<0.001
n=12,562
0.02
0.00
0
3
6
Months of Follow-up
Yusuf S et al. N Engl J Med. 2001;345:494-502.
9
12
CURE: Long-term Benefit of Clopidogrel
12,562 Patients with NSTEACS (mostly conservatively managed)
CV Death, MI, or Stroke
First 30 Days
CV Death, MI, or Stroke
>30 Days–1 Year
1.00
Proportion Event-Free
Proportion Event-Free
1.00
Clopidogrel
0.98
0.96
Placebo
0.94
RRR: 21%
95% CI, 0.67–0.92
P=0.003
0.92
0.90
Week
Clopidogrel
Placebo
0
6259
6303
1
2
6145
6159
No. at Risk
6070
6048
Yusuf S et al. Circulation. 2003;107:966-972.
Clopidogrel
0.98
0.96
Placebo
0.94
RRR: 18%
95% CI, 0.70–0.95
P=0.009
0.92
0.90
3
6026
5993
4
5990
5965
Month
1
5981
5954
4
5481
5390
6
8
No. at Risk
4742 4004
4639 3929
10
12
3180
3159
2418
2388
CURE: Life-threatening Bleeding
Placebo + ASA*
n = 6303
(%)
Life-threatening
Clopidogrel + ASA*
n = 6259
(%)
1.8
2.2 (P = 0.13)
Fatal
0.2
0.2
5 g/dL drop hemoglobin
0.9
0.9
Hypotension-inotropic therapy
0.5
0.5
Surgery required
0.7
0.7
Hemorrhagic stroke
0.1
0.1
≥4 blood units
1.0
1.2
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CHARISMA: Primary Outcome
ASA vs ASA + Clopidogrel in 1º and 2º
Atherothrombosis Prevention
Death, MI, or Stroke (%)
8
Placebo + ASA*
7.3%
Symptomatic (n=12,153)
HR 0.88 (0.77 – 0.998, P=0.046)
Clopidogrel + ASA*
6.8%
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
P=0.22
2
n=15,603
0
0
6
12
18
Months since randomization
*All patients received ASA 75-162 mg/day
Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.
24
30
CHARISMA
A post hoc Exploratory Analysis
CAD without Prior MI
23% Risk Reduction if Prior MI
23% risk
reduction if
prior MI
Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.
CHARISMA: Primary Endpoint (MI/Stroke/CV Death)
in Patients With Previous MI, IS, or PAD*
“CAPRIE-like Cohort”
Primary Outcome Event Rate (%)
10
n=9,478
8.8%
Placebo + ASA
Clopidogrel + ASA
8
7.3%
6
4
RRR: 17.1 % (95% CI: 4.4%, 28.1%)
P=0.01
2
* Post hoc analysis.
0
0
6
12
18
24
Months Since Randomization
Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.
30
CHARISMA
Timing of Severe or Moderate Bleeding
0.00008
Placebo + ASA
Clopidogrel + ASA
Hazard Function/d
0.00007
0.00006
0.00005
0.00004
0.00003
0.00002
0.00001
0
15 60
135
270
450
Days Since Randomization
Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.
630
810
CURRENT-OASIS 7:
Double versus Standard Dose Clopidogrel
Primary Efficacy and Safety Outcomes
Standard
Double
HR
95% CI
P
PCI (2n=17,232)
4.5%
3.9%
0.85 0.74-0.99 0.036
No PCI (2n=7855)
4.2%
4.9%
1.17 0.95-1.44
Overall (2n=25,087)
4.4%
4.2%
0.95 0.83-1.06 0.300
TIMI Major*
1.3%
1.7%
1.26
l.03- 1.54
0.03
CURRENT Major**
2.0%
2.5%
1.24 1.05- 1.46
0.01
Intn P
CV Death/MI/Stroke
0.14
0.016
Major Bleeding
ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
** Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
*
Mehta SR et al. N Engl J Med. 2010;363:930-942.
2º PREVENTION:
Antithrombotic Therapies
P2Y12 Inhibition – Prasugrel
TRITON-TIMI 38 Efficacy and Safety
Type of MI by Prasugrel vs Clopidogrel
16
138
events
14
12
Clopidogrel
CV Death/MI/Stroke
9.9
Endpoint
(%)
10
Prasugrel
8
6
TIMI Major
Non-CABG Bleeds
4
Prasugrel
2
0
12.1
Clopidogrel
0
30
60
90
180
270
Days After Randomization
CABG = coronary-artery bypass surgery; NNH = number needed to harm;
NNT = number needed to treat; TIMI = Thrombolysis in Myocardial Infarction.
All Cause Mortality: Clopidogrel 3.2%, Prasugrel 3.0%, P = 0.64.
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
360
2.4
1.8
450
HR 0.81
(0.73-0.90)
P < 0.001
NNT = 46
HR 1.32
(1.03-1.68)
P = 0.03
NNH = 167
35
events
Prasugrel vs Clopidogrel According to
Clinical Scenario
Scirica BM et al. J Am Coll Cardiol. 2012;59:E340.
TRITON TIMI 38: Net Clinical Benefit
Prasugrel vs Clopidogrel Subgroups; Post hoc Analysis
Risk (%)
Prior
Stroke / TIA
Yes
Age
≥75
+ 54
No
Pint = 0.006
-1
-16
Pint = 0.18
<75
Weight
+3
<60 kg
≥60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
-16
Prasugrel
Better
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
1
HR
Clopidogrel
Better
2
39
TRILOGY: Primary Efficacy Endpoint and
TIMI Major Bleeding Through 30 Months
Endpoint (%)
(Age <75 years, n = 7243)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
HR (95% CI):
1.31 (0.81, 2.11)
P = 0.27
Roe MT et al. N Engl J Med. 2012;367:1297-1309.
TRILOGY: Primary Efficacy Endpoint to 900 Days
Prasugrel vs. Clopidogrel in Medically Managed ACS
Subanalysis: Angiography versus No Angiography
Angiography
n=3085
No Angiography
n=4158
16.3% vs 16.7%
P = 0.954
10.7% vs 14.9%
P = 0.031
HR (95% CI):
1.01 (0.84, 1.20)
HR (95% CI):
0.77 (0.61, 0.98)
P interaction = 0.08
Wiviott SD et al. Lancet. 2013;382:605-613.
2º PREVENTION:
Antithrombotic Therapies
P2Y12 Inhibition – Ticagrelor
PLATO: Kaplan-Meier Estimate of Time to First Primary
Cumulative incidence (%)
Efficacy Event (Composite of CV Death, MI, or Stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Clopidogrel
9.8
Ticagrelor
HR = hazard ratio
CI = confidence interval
HR 0.84 (95% CI 0.77–0.92), P=0.0003
0
No. at risk
Ticagrelor
Clopidogrel
11.7
60
120
180
240
300
360
5,161
5,096
4,147
4,047
Days after randomisation
9,333
9,291
8,628
8,521
8,460
8,362
Wallentin L et al. N Engl J Med. 2009;361:1045-1057.
8,219
8,124
6,743
6,743
PLATO: Secondary Efficacy Endpoints Over Time
Myocardial Infarction
Cardiovascular Death
HR 0.82 (95% CI, 0.68-0.98) P=0.025
8
6.59
Clopidogrel
6
5.26
4
Ticagrelor
2
0
0
60
120
180
240
300
360
Cumulative incidence (%)
Cumulative incidence (%)
HR 0.80 (95% CI, 0.69-0.92) P=0.002
8
6
4
3.44
2
0
Ticagrelor
0
60
Time After Randomisation
(Days)
Wallentin L et al. N Engl J Med. 2009;361:1045-1057.
4.33
Clopidogrel
120
180
240
300
360
PLATO
INITIAL NON-INVASIVE
STRATEGY SUBGROUP
INVASIVE STRATEGY GROUP
Primary endpoint:
CV death, MI, or stroke
Cannon CP et al. Lancet 2010;375:288-293
PLATO: Stent Thrombosis
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
HR for ticagrelor
(95% CI)
P value*
Definite
1.0
1.6
0.62 (0.45–0.85)
0.003
Probable or definite
1.7
2.3
0.72 (0.56–0.93)
0.01
Possible, probable, or definite
2.2
3.1
0.72 (0.58–0.90)
0.003
Stent thrombosis, %
Evaluated in patients with any stent during the study
Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization
* By univariate Cox model
¶
Cannon CP et al. Lancet. 2010;375:283-293.
PLATO Invasive:
Time from CABG to Primary Endpoint
K-M estimated rate (%)
CV death, MI, or stroke (CABG population)
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0 0
No. at risk
Ticagrelor
Clopidogrel
629
629
Clopidogrel
13.1
10.6
Ticagrelor
HR: 0.84 (95% CI = 0.60–1.16), P=0.29
1
2
3
543
541
Held C et al. J Am Coll Cardiol. 2011;567:672-684.
4
5
6
7
8
Months from CABG procedure
519
516
458
448
386
386
9
10
268
255
11
12
108
125
PLATO
Non-CABG and CABG-related Major Bleeding
NS
8
7.9
Ticagrelor
Clopidogrel
7.4
K-M estimated rate (% per year)
7
NS
6
5.3
P=0.026
5
4
5.8
4.5
3.8
P=0.025
2.8
3
2.2
2
1
0
Non-CABG
PLATO major bleeding
Wallentin L et al. N Engl J Med. 2009;361:1045-1057.
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
2º PREVENTION:
Antithrombotic Therapies
PAR-1 Thrombin Inhibitor – Atopaxar
LANCELOT-ACS: Atopaxar
Incidence of CV Death, MI, or Stroke
12.0%
10.0%
8.0%
6.0%
5.7%
5.6%
4.0%
3.3%
2.0%
1.9%
2.0%
0.0%
Placebo
RR (95% CI) vs
placebo
Active combined
atopaxar
RR 0.58 (0.25-1.41)
P = 0.20
O’Donoghue M et al. Circulation. 2011;123:1843-1853.
50mg QD
RR 0.34 (0.10-1.18)
P = 0.10
100mg QD
200mg QD
RR 1.02 (0.41-2.50)
P = 0.99
RR 0.36 (0.11-1.24)
P = 0.12
LANCELOT-ACS
Incidence of Holter-Detected Ischemia
48 Hours following 400mg Loading Dose
30.0%
28.1%
RR 0.67 (95% CI 0.48-0.94)
P = 0.02
25.0%
20.0%
18.7%
15.0%
10.0%
n=128
n=433
5.0%
0.0%
Placebo
O’Donoghue M et al. Circulation. 2011;123:1843-1853.
Active combined atopaxar
LANCELOT-ACS: Atopaxar
Incidence of Any TIMI Bleeding
14%
TIMI minimal
TIMI minor
TIMI major
12%
10%
8%
6%
8.3%
9.4%
7.3%
6.2%
7.2%
4%
1.3%
2%
0%
P trend = 0.63
0.7%
0.7%
1.3%
0.7%
Placebo
Active combined atopaxar
50mg QD
100mg QD
200mg QD
n=138
n=455
n=153
n=156
n=146
RR (95% CI)
vs placebo
RR 0.91 (0.52-1.63)
P = 0.77
O’Donoghue M et al. Circulation. 2011;123:1843-1853.
2.6%
1.4%
RR 0.77 (0.38-1.60) RR 1.20 (0.63-2.29) RR 0.74 (0.35-1.56)
P = 0.53
P = 0.60
P = 0.46
2º PREVENTION:
Antithrombotic Therapies
Factor Xa Inhibitor – Rivaroxaban
RIVAROXABAN: ATLAS ACS 2 TIMI 51
Primary Efficacy Endpoint: CV Death / MI / Stroke
12
2 Yr KM Estimate
Placebo*
10
10.7%
8.9%
8
6
Rivaroxaban*
4
mITT P=0.008
ITT P=0.002
(both doses
2.5 mg bid and 5 mg bid)
2
0
HR 0.84
(0.74-0.96)
ARR 1.8%
NNT=56
0
No. at Risk
5113
Placebo
Rivaroxaban 10229
4
8
12
16
20
24
1079
2084
421
831
Months After Randomization
4307
8502
*with clopidogrel in majority of patients
Mega JL et al. N Engl J Med. 2012;366:9-19.
3470
6753
2664
5137
1831
3554
RIVAROXABAN: ATLAS ACS 2 TIMI 51
Efficacy Endpoints: Very Low Dose 2.5 mg BID
Patients Treated with Aspirin + Thienopyridine
CV Death / MI / Stroke
Cardiovascular Death
5%
HR 0.84
12%
Placebo
HR 0.66
9.0%
mITT
P<0.001
Placebo
4.2%
10.4%
Estimated Cumulative incidence (%)
mITT
P=0.04
ITT
P=0.01
ITT
P<0.001
2.5%
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 59
NNT = 71
0
12
Months
Mega JL et al. N Engl J Med. 2012;366:9-19.
24
0
12
Months
24
RIVAROXABAN: ATLAS ACS 2 TIMI 51
Treatment Emergent Fatal Bleeds and ICH
1.2
1
P = NS for Riva vs Placebo
P = NS for Riva 5 vs Placebo
P = NS for Riva 2.5 vs Placebo
P = 0.044 for Riva 2.5 vs 5
P = 0.009 for Riva vs Placebo
P = 0.005 Riva 5 vs Placebo
P = 0.037 for Riva 2.5 vs Placebo
P = 0.44 for Riva 2.5 vs 5
0.8
Placebo
2.5 mg Rivaroxaban
5.0 mg Rivaroxaban
0.7
P = NS for all
comparisons
0.6
0.4
0.4
0.2
0
0.2
0.4
0.2
0.2
0.1
0.1
n=9
n=6 n=15
n=5 n=14 n=18
Fatal
ICH
ICH: intracranial hemorrhage
Adapted from Mega JL et al. N Engl J Med. 2012:336:9-19.
n=4
0.1
n=5 n=8
Fatal ICH
Rivaroxaban – Clinical Trial Design of
COMPASS: Prevention of MI, Stroke, or Cardiovascular
Death in Patients with CAD or PAD
Clinicaltrials.gov
ANTITHROMBOTIC THERAPIES:
Longer-term Protection
P2Y12 Antagonists
DAPT Study: Continuation of Thienopyridine
12 Months after PCI: Efficacy
Death, MI, or Stroke
(65% Clopidogrel; 35% prasugrel)
n=9961
26% with MI
50.9% w/ ≥1 risk factor for ST
47% everolimus stent
Stent
Thrombosis
Mauri L et al. N Engl J Med. 2014;371:2155-2166.
DAPT Study: Continuation of Thienopyridine
12 Months after PCI: Safety
50% increase
in GUSTO
Mod/Sev
Mortality
Mauri L et al. N Engl J Med. 2014;371:2155-2166.
Risk of Cardiovascular and Bleeding Endpoints
Comparing Extended Dual Antiplatelet Therapy vs Aspirin Alone
Udell JA et al. Eur Heart J. 2015. pii: ehv443. [Epub ahead of print].
PEGASUS-TIMI 54: Ticagrelor
Primary Endpoint
10
n = 21,162
Median follow-up 33 months
CV Death, MI, or Stroke (%)
9
Placebo (9.04%)
8
Ticagrelor 90 (7.85%)
Ticagrelor 60 (7.77%)
7
6
5
Ticagrelor 90 mg
HR 0.85 (95% CI 0.75 – 0.96)
P=0.0080
4
3
Ticagrelor 60 mg
HR 0.84 (95% CI 0.74 – 0.95)
P=0.0043
2
1
0
0
3
6
9
12
15
18
21
24
27
Months from Randomization
Bonaca MP et al. N Engl J Med. 2015;372:1791-1800.
30
33
36
PEGASUS-TIMI 54:
Components of Primary Endpoint
Endpoint
HR (95% CI)
P value
0.85 (0.75-0.96)
0.008
CV Death, MI, or Stroke
0.84 (0.74-0.95)
0.004
(1558 events)
0.84 (0.76-0.94)
0.001
0.87 (0.71-1.06)
0.15
CV Death
0.83 (0.68-1.01)
0.07
(566 events)
0.85 (0.71-1.00)
0.06
0.81 (0.69-0.95)
0.01
Myocardial Infarction
0.84 (0.72-0.98)
0.03
(898 events)
0.83 (0.72-0.95)
0.005
0.82 (0.63-1.07)
0.14
Stroke
0.75 (0.57-0.98)
0.03
(313 events)
0.78 (0.62-0.98)
0.03
0.4
0.6
0.8
Ticagrelor better
Bonaca MP et al. N Engl J Med. 2015;372:1791-1800.
1
1.25
Placebo better
1.67
Ticagrelor 90 mg
Ticagrelor 60 mg
Pooled
PEGASUS: Bleeding
5
3-Year KM Event Rate (%)
4
Ticagrelor 90: HR 2.69 (1.96-3.70)
Ticagrelor 60: HR 2.32 (1.68-3.21)
Ticagrelor 90 mg
Ticagrelor 60 mg
Placebo
P<0.001
3
2.6
2.3
P<0.001
2
1.1
1
1.3
1.2
0.4
0
TIMI Major
Bonaca MP et al. N Engl J Med. 2015;372:1791-1800.
TIMI Minor
ANTITHROMBOTIC THERAPIES:
Longer-term Protection
PAR-1 Antagonist – Vorapaxar
Vorapaxar
Secondary Prevention (FDA Approval Population)
Bleeding
GUSTO Mod/Sev at 3 yrs
3.7 v. 2.4%, HR 1.55, P<0.001
9.5%
Placebo
Event Rate (%)
7.9%
CV Death, MI, or Stroke
n = 20,170
MI or PAD
(No hx stroke/TIA)
Vorapaxar
Hazard Ratio 0.80;
95% CI 0.73 to 0.89
P<0.001
ARD 1.6%, NNT 63
Days from Randomization
Magnani G et al. J Am Heart Assoc. 2015;4:e001505.
Morrow DA et al. N Engl J Med. 2012;366:1404-1413.
Vorapaxar: Secondary Prevention (MI Cohort)
Death from Cardiovascular Causes, Myocardial Infarction, or Stroke
Days 0 to 360
Day 360 to 1080
7%
7%
HR 0.79
P = 0.003
CV Death / MI / Stroke (%)
6%
HR 0.82
P = 0.004
6%
Placebo
6.5%
5%
5%
4.0%
Placebo
4%
5.5%
4%
Vorapaxar
3%
3%
2%
3.2%
Vorapaxar
1%
2%
1%
0%
0%
0
90
180
270
Days since randomization
Scirica BM et al. Lancet. 2012;380:1317-1324.
360
360
450
540
630
720
810
900
Days since randomization
990
1080
Optimal Duration of DAPT?
Eisen A, Bhatt DL. Nat Rev Cardiol. 2015, Epub ahead of print.
Guideline Recommendations
Duration of P2Y12 Inhibitor Therapy after ACS
Society
Management Recommended Duration
Medical
PCI (DES)
All
Medical
PCI
ACCP
Ideally up to 12 months
At least 12 months
12 months
“Data suggest … SES or PES … may benefit from
prolonged DAPT beyond 1 year.”
“… data suggest that DAPT for 6 mos might be
sufficient because late and very late ST correlate
poorly with d/c of DAPT.”
12 months
12 months
(After 12 mos, recommend single antiplatelet therapy
over continuation of DAPT)
Amsterdam EA et al. J Am Coll Cardiol. 2014;64:e139-e228
Hamm CW et al. Eur Heart J. 2011;32:2999-3054
Vandick PO et al. Chest. 2012;141:e6375-e6685
2012 ACCF/AHA Focused Update on UA/NSTEMI
Clopidogrel, Prasugrel, Ticagrelor
Clopidogrel
Management
strategy
Conservative
Invasive
Loading dose
300 mg
Load timing
Prasugrel
Conservative
Ticagrelor
Invasive
Conservative
Invasive
600 mg
60 mg at PCI
180 mg
180 mg
on presentation
asap pre-PCI
known anatomy
on
presentation
asap
pre-PCI
Maintenance
75 mg/day
75 mg/day
10 mg daily
90 mg bid
90 mg bid
Duration Med
Up to 12 mo
Up to 12 mo
Duration BMS
Up to 12 mo
Up to 12 mo
Up to 12 mo
Duration DES
≥12 mo
≥12 mo
≥12 mo
Jneid H et al. J Am Coll Cardiol. 2012;60:645-681.
Antithrombotic Agents:
Comparative Clinical Attributes
• Clopidogrel (P2Y12 antagonist)
– Double-dose (600 mg load, 150 mg qd x 1 week) in PCI decreases non-fatal MI, stent
thrombosis
– Much data supporting use of P2Y12 inhibitor in patients with h/o TIA/stroke
– Longer-term protection (CHARISMA, CAPRIE, DAPT)
• Prasugrel (P2Y12 antagonist)
–  ischemic events c/w clopidogrel, both early and late, c/w clopidogrel
–  stent thrombosis c/w clopidogrel
– Especially large benefit in diabetics and in STEMI
– Not superior to clopidogrel in medically managed patients
– Contraindicated in patients with h/o TIA/stroke
– Longer-term protection (DAPT)
• Ticagrelor (P2Y12 antagonist)
–  ischemic events c/w clopidogrel; early and late, with invasive and conservative management
–  stent thrombosis c/w clopidogrel
–  CV mortality c/w clopidogrel, including with CABG
– Longer-term protection (PEGASUS)
• Vorapaxar (PAR-1 antagonist)
– Approved tor patients with a history of ACS
– Longer-term protection (TRA 2oP)
Antithrombotics in Longer-term 2º Prevention:
Current/Future Issues and Opportunities
Switching; concomitant therapies
Customizing therapies to patient needs
Other high-risk populations; new indications
Participant CME Evaluation
• Please take out the Participant CME Post-survey and
Evaluation Form from the back of your packet.
• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few post-activity survey questions measuring the
knowledge and competence you have garnered from this
program. The post-survey begins on page 1 of the
evaluation form.
• Your participation will help shape future CME activities.
Polling Question
Post-activity Survey
Following a myocardial infarction, risk of ischemic events is
increased for:
A. the following month
B. up to 6 months
C. up to a year
D. longer than a year
E. there are insufficient data to draw conclusions
Polling Question
Post-activity Survey
Results from multiple clinical trials indicate that P2Y12
antagonists reduce the absolute number of ischemic events:
A. equally for high-risk and low-risk patients
B. more for high-risk patients than low-risk patients
C. more for low-risk patients than high-risk patients
D. there are insufficient clinical data to determine
Polling Question
Post-activity Survey
In the initial medical management of patients with ACS, how
long do current professional society guidelines recommend
the use of dual antiplatelet therapy?
A. 30 days
B. 3 months
C. 6 months
D. 12 months
E. Indefinitely
Polling Question
Post-activity Survey
Longer-term (>1 year) dual antiplatelet therapy (ASA +
P2Y12 inhibitor or PAR-1 inhibitor) results in reduction of
recurrent ischemic events and:
A. reduced bleeding risk
B. unchanged bleeding risk
C. transient (6-month) increased bleeding risk
D. sustained increased bleeding risk
Polling Question
Post-activity Survey
Protease-activated receptor 1 (PAR-1) direct thrombin
inhibition describes the mechanism of antithrombotic action
of:
A. clopidogrel
B. prasugrel
C. rivaroxaban
D. ticagrelor
E. vorapaxar
Thank you for joining us today!
Supplemental slides