Transcript PEGASUS-TIMI 54 - accpcardsprnjournalclub

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The Prevention of Cardiovascular Events in Patients
with Prior Heart Attack Using Ticagrelor Compared to
Placebo on a Background of Aspirin-Thrombolysis in
Myocardial Infarction (PEGASUS-TIMI 54)
Sheena Mathew, Pharm.D.
May 29, 2015
Disclosure Statement: Presenters have no conflicts
to report related to financial or personal relationships
with commercial entities (or their competitors) that
may be referenced in this presentation
Background
• Patients with myocardial infarction (MI) have
higher risk for recurrent ischemic events
• Activated platelets responsible for
cardiovascular (CV) ischemic risk
• Use of dual-antiplatelet therapy (DAPT) with
aspirin and a P2Y12 inhibitor can help reduce
the risk of ischemic events in the first year
after acute coronary syndrome (ACS)
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Background: PLATO Trial
• Multi-center randomized double-blind trial
• Compared clopidogrel (loading dose 300-600 mg,
maintenance dose 75 mg daily) to ticagrelor (loading dose 180
mg, maintenance dose 90 mg twice daily)
– In addition to aspirin 75-325 mg
• Patient Population: All ACS patients, with or without STsegment elevation with an onset of symptoms in the previous
24 hours
• Primary endpoint: composite of death from vascular causes,
MI, or stroke
Wallent L, et al. NEJM. 2009; 361 (11):1045-1057.
Background: PLATO Trial
Outcome
Primary outcome:
Ticagrelor vs. Clopidogrel, Hazard Ratio
(95% CI)
P-Value
9.8 % vs 11.7, 0.84 (0.77-0.92)
<0.001
Death from any cause, MI, or stroke
10.2% vs. 12.3%, 085 (0.77-0.92)
<0.001
Death from vascular causes, MI,
stroke, severe recurrent ischemia, TIA
or other arterial thrombotic event
14.6% vs. 16.7%, 0.88 (0.81-0.95)
<0.001
MI
5.8% vs. 6.9%, 0.84 (0.75-0.95)
0.005
Death from any cause
4.5% vs. 5.9%, 0.78 (0.69-0.89)
<0.001
Stent thrombosis-definite
1.3% vs. 1.9%, 0.67 (0.50-0.91)
0.009
TIMI Major Non-CABG Bleeding
2.8% vs. 2.2%, 1.25 (1.03-1.43)
0.03
PLATO Major Non-CABG Bleeding
4.5% vs. 3.8%, 1.19 (1.02-1.38)
0.03
Dyspnea-Any
13.8% v.s 7.8%, 1.84 (1.68-2.02)
<0.001
Secondary Endpoints:
Adverse Events
Wallent L, et al. NEJM. 2009; 361 (11):1045-1057.
Background
Treatment with DAPT Beyond 12 Months
Trial
Outcomes
DAPT Trial
•
•
•
Trilogy-ACS Trial
•
•
•
•
Compared continued thienopyridine vs aspirin alone for 30 months
Statistically significant difference in the decrease of the primary outcome
in the continued thienopyridine group:
• Stent-thrombosis
• MACCE: Death, MI
Statistically significant increase in bleeding in the continued
thienopyridine group (based on the GUSTO criteria and the BARC criteria)
Compared the use of 30 months of DAPT with prasugrel vs. clopidogrel for
30 months in patients with unstable angina or MI without ST-segment
elevation and did not undergo revascularization
Prasugrel did not significantly reduce the primary endpoint of death from
CV causes, MI, or stroke
The incidence of bleeding occurred with similar frequency in both groups
(based on the GUSTO criteria) in both age <75 years and overall
population
Slight increase in the prasugrel group in the TIMI criteria for major or
minor bleed in patients <75 years of age
Maur L, et al. NEJM. 2014; 371(23):2155-2166.
Roe mT, et al. NEJM. 2012; 367 (14): 1297-1309.
Background
Treatment with DAPT Beyond 12 Months
Trial
Outcomes
CHARISMA Trial • DAPT with clopidogrel + low-dose aspirin vs. aspirin alone in
patients with high-risk atherthrombotic events
• There was no difference between the two groups in the primary
efficacy end point of first occurrence of MI, stroke, or death from
CV causes
• Statistically significant increase in moderate bleeding based on the
GUSTO definition in the clopidogrel group vs. the placebo group
Bhatt DL, et al. NEJM. 354(16):1706-1717.
Background
Minimum Duration of DAPT
Drug-Eluting Stent (DES)
• ACCF/AHA/SCAI (2011)
• 12 months
• ESC (2014)
• 6 months in stable coronary
artery disease (CAD)
• 12 months for ACS
indications
Levine G, et al. Circulation. 2011; 124(23): e574-e651
Windecker S, et al. Eur Heart J. 2014; 35:2541-619
Bare Metal Stent (BMS)
• ACCF/AHA/SCAl (2011)
• 1 month in non-ACS
indication
• 12 months for ACS indication
• ESC (2014)
• 1 month in stable CAD
• 12 months for ACS indication
Background & Purpose
• Randomized, Double-Blind, placebo-controlled
clinical trial
• Purpose:
– To test whether long-term therapy with ticagrelor
added to low-dose aspirin reduces the risk of
major CV events among stable patients with a
history of MI.
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Study-Design
Inclusion Criteria
• Spontaneous MI 1-3 years before
enrollment
• Age ≥ 50 years
• One of the following additional high-risk
features:
• Age of 65 years or older
• Diabetes mellitus requiring
medications
• A second prior spontaneous MI
• Multivessel CAD
• Chronic renal dysfunction (CrCl<60
ml/min)
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Exclusion Criteria
• Planned use of a P2Y12 receptor
antagonist, dipyridamole, cilostazol, or
anticoagulant therapy during the study
period
• Bleeding disorder history
• History of ischemic stroke
• History of intracranial bleed
• Central nervous system tumor
• Intravascular abnormality
• Gastrointestinal (GI) bleed within the
previous 6 months
• Major surgery within the previous 30
days
• Renal failure requiring dialysis
• Concomitant use of potent
inducer/inhibitor/substrate of CYP3A4
Study-Design
Treatment Arms: Study Duration-3 years
Arm 1
(n=7050)
Arm 2
(n=7045)
• Aspirin 75150 mg daily
• Ticagrelor 90
mg twice
daily
• Aspirin 75150 mg daily
• Ticagrelor 60
mg twice
daily
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Arm 3
(n=7067)
• Aspirin 75150 mg daily
• Placebo
Statistical Analysis
• Power:
– 90-mg dose vs. placebo for the primary endpoint:
1360 events for 90% power to detect a 20% reduction
– 60-mg dose vs. placebo for the primary endpoint:1360
events to provide 83% power to detect a 19%
reduction
• Event probabilities:
– Kaplan-Meier estimates of cumulative incidence at 36
months
• Hazard ratios:
– Generated using Cox proportional hazard model
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Study-Design
Primary Endpoint
• Composite of CV death, MI, or stroke
Secondary Endpoint • CV death and death from any cause
• Composite endpoint of death from coronary heart disease, MI,
or stroke
• Individual components of the composite endpoints
• Urgent coronary revascularization
• Hospitalization for unstable angina
• Transient ischemic attack (TIA)
Safety Endpoint
• Major Bleeding based on the thrombolysis of myocardial
infarction (TIMI) definition
• Intracranial hemorrhage
• Fatal bleeding
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Patient Demographics
Characteristic
Ticagrelor, 90 mg
(N=7050)
Ticagrelor, 60 mg
(N=7045)
Placebo
(N=7067)
65.4±8.4
65.2±8.4
65.4±8.3
Multivessel CAD1no/total no. (%)
4155/7049 (58.9)
4190/7042 (59.5)
4213/7067 (59.6)
History of PCI-no. /total
no. (%)
5852/7049 (83.0)
5879/7044 (83.5)
5837/7066 (82.6)
>1 Prior MI –no. (%)
1143 (16.2)
1168 (16.6)
1188 (16.8)
Years since MI-Median
(IQR)
1.7 (1.7-2.3)
1.7 (1.2-2.3)
1.7 (1.2-2.3)
STEMI
3753/7043 (53.4)
3757/7035 (53.4)
3809/7057 (54.0)
NSTEMI
2898/7043 (41.1)
2842/7035 (40.4)
2843/7057 (40.3)
382/7043 (5.4)
436/7035 (6.2)
405/7057 (5.7)
7039 (99.8)
7036 (99.9)
7057 (99.9
Age
Type of MI-no. (%)
Unknown
Aspirin at any dose-no.
(%)
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Results
Endpoint
Ticagrelor 90 mg vs. Placebo; %
(HR, 95% CI; P-value)
Ticagrelor 60 mg. vs. Placebo; %
(HR, 95% CI; P-value)
CV Death, MI, or
Stroke
7.85 vs. 9.04 (0.85, 0.75-0.96,
p=0.008)
7.77 vs. 9.04 (0.84, 0.74-0.95,
p=0.004)
Death from CHD1,
MI, or stroke
6.99 vs. 8.33 (0.82, 0.72-0.93,
p=0.002)
7.09 vs. 8.33 (0.83, 0.73-0.94,
p=0.003)
CV death or MI
6.79 vs. 7.81 (0.85, 0.75-0.97,
p=0.01)
6.77 vs. 7.81 (0.85, 0.74-0.96,
p=0.01)
Death from CHD,
or MI
5.59 vs. 6.68 (0.81, 0.71-0.94,
p=0.004)
5.75 vs. 6.68 (0.84, 0.73-0.96,
p=0.01)
CV death
2.94 vs. 3.39 (0.87, 0.71-1.06,
p=0.15)
2.86 vs. 3.39 (0.83, 0.68-1.01,
p=0.07)
1Coronary
heart disease
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Results
Outcome
Ticagrelor 90 mg vs. Placebo; %
(HR, 95% CI; P-value)
Ticagrelor 60 mg. vs. Placebo; %
(HR, 95% CI; P-value)
Death from CHD
1.53 vs. 2.08 (0.73, 0.56-0.95,
p=0.02)
1.72 vs. 2.08 (0.80, 0.62-1.04,
0.09)
MI
4.40 vs. 5.25 (0.81, 0.69-0.95,
p=0.01)
4.53 vs. 5.25 (0.84, 0.72-0.98,
p=0.03)
Stroke- Any
1.61 vs. 1.94 (0.82, 0.63-1.07,
0.14)
1.47 vs. 1.94 (0.75, 0.57-0.98,
p=0.03)
Death from any
cause
5.15 vs. 5.16 (1.00, 0.86-1.16,
p=0.99)
4.69 vs. 5.16 (0.89, 0.76-1.04,
p=0.14)
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Results
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Results
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Results
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Author’s Conclusion
Addition of ticagrelor at a dose of 90-mg twice
daily or 60-mg twice daily, to low-dose aspirin
reduced the risk of CV death, MI, or stroke and
increased the risk of TIMI major bleeding among
patients who had an MI 1-3 years later
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Discussion
• Use of ticagrelor with low-dose aspirin in patients 13 years after MI significantly reduced the risk of CV
death, MI, or stroke
• Rates of discontinuation due to dyspnea of ticagrelor
in the 90-mg group vs. the 60-mg was higher
– displaying a more attractive benefit-risk profile in the
60-mg group
• Longer duration of ticagrelor treatment was
associated with an increased risk of bleeding
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Discussion
• PEGASUS-TIMI 54 compared to other long-term
studies DAPT, Trilogy-ACS, and CHARISMA
– varying data on extended-use of DAPT
– mixed patient population
• Vorapaxar has been recently approved:
– Reduction of thrombotic events in MI and peripheral
arterial disease
– Possible benefit for extended-use of DAPT
• Usage of these agents will come with risk of
bleed
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Morrow DA., et al. NEJM. 2012;366:1404-1413.
Discussion
Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.
Critique
Strengths
Limitations
• Study Design
• Excluded other antiplatelet
agents and anticoagulants
• Studied a lower-dose of
ticagrelor (i.e. 60 mg twice
daily)
• Endpoints appropriately
powered
• Rates of discontinuation
due to bleeding and
dyspnea down-played
• Did not disclose patient
population bleeding history
Practical Implications
• Displays the benefit and effect of DAPT with ticagrelor and
aspirin in patients who had an MI in the previous 1-3 years
• Must assess the risk of bleed vs. the benefit in utilization of
extended use of dual antiplatelet therapy
– NNT: 90 mg: 84, 60 mg: 79
– NNH: 90 mg: 64, 60 mg: 81
• 60 mg tablet strength not available
– FDA recently accepted priority review of ticagrelor 60 mg tablet
– If approved potential benefit of using 60-mg twice daily dose
instead of the 90-mg twice daily dose
Acknowledgements
• Journal Club Mentor:
– Carrie Oliphant, Pharm.D., BCPS-AQ Cardiology
• Program Directors:
– ACCP Cardiology PRN Journal Club Coordinator:
• Craig Beavers, Pharm.D., FAHA, AACC, BCPS-AQ
Cardiology, CACP
– Elizabeth McNeely, Pharm.D., BCPS-AQ Cardiology
The Prevention of Cardiovascular Events in Patients
with Prior Heart Attack Using Ticagrelor Compared to
Placebo on a Background of Aspirin-Thrombolysis in
Myocardial Infarction (PEGASUS-TIMI 54)
Sheena Mathew, Pharm.D.
May 29, 2015
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