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Article Title/Citation,
Journal, Authors,
Affiliation
BACKGROUND AND OVERVIEW
Article Title:
“Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction.”
(PEGASUS-TIMI54)
Journal: The New England Journal of Medicine (NEJM)
Published: May 7, 2015
Authors: Bonaca M, Bhatt D, Cohen M, et al.
Affiliations:
The Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of
Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston; the Cardiovascular Division,
Department of Medicine, Newark Beth Israel Medical Center, Rutgers–New Jersey Medical School, Newark;
French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire Fibrosis, Inflammation,
Remodeling, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, INSERM Unité 1148, and Université Paris–
Diderot, Sorbonne Paris Cité — all in Paris; National Heart and Lung Institute, Royal Brompton Hospital,
Imperial College, London, and Department of Cardiovascular Science, University of Sheffield, Sheffield, United
Kingdom; AstraZeneca, Mölndal, Sweden; Icahn School of Medicine at Mount Sinai, New York; Canisius–
Wilhelmina Hospital, Nijmegen, the Netherlands; Postgraduate Medical School, Grochowski Hospital, Warsaw,
Poland; Montreal Heart Institute, Université de Montréal, Montreal; Cardiology Research Center, Moscow;
Kerckhoff Heart Center, Bad Nauheim, and University of Giessen, Giessen — both in Germany; Department of
Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan; University Hospital, Jihlavska,
Brno, Czech Republic; Heart Institute (InCor)–University of São Paulo Medical School, São
Paulo; and the Department of Cardiology, Military Hospital, Budapest, Hungary.
Study
objectives/purpose
Brief background
Funding sources and
disclosures
Study design and
methodology
To determine if the addition of Ticagrelor, a P2Y12 receptor antagonist, to standard
therapy would be beneficial long-term in patients who have previously experienced a
myocardial infarction.
Current ACS guidelines recommend the use of dual anti-platelet therapy (DAPT) in
patients who have experienced a myocardial infarction (MI) for up to one year. These
recommendations include Aspirin (Class I,LOE-A) and a P2Y12 receptor antagonist (Class
I, LOE-B). It is important to note that the guidelines do mention that DAPT therapy >12
months can be considered in patients undergoing stent treatment (Class IIb, LOE-C). In a
post hoc analysis of CHARISMA, it was determined that longer treatment with dual antiplatelet therapy reduced ischemic events in patients with prior MI. Also, notably in the
PLATO trial, Ticagreor was compared against Clopidogrel in the reduction of combined
primary end point of cardiovascular (CV) death, myocardial infarction (MI), or stroke, and
showed to have a significant reduction vs Clopidogrel, while not having any significant
increase in major bleeding.
Funding/Source(s):
AstraZeneca
METHODS
Randomized, double-blind, placebo-controlled clinical trial.
Randomization took place in 31 countries at 1,160 sites
Patient selection &
enrollment [
Medium follow-up time was 33 months
Inclusion Criteria:
o Spontaneous Myocardial Infarction 1-3 years prior
o At least 50 years old
o Including one additional high risk factor:
 ≥ 65 years old
 Diabetes Mellitus requiring medication
 Second prior spontaneous Myocardial Infarction
 Chronic Renal Dysfunction- CrCl < 60 mL/min
 Multivessel Coronary Artery Disease
o Able to tolerate Aspirin
Study interventions
Outcome measures/
endpoints
Exclusion Criteria:
o Planned use of:
 P2Y12 Receptor Antagonist
 Dipyridamole
 Cilostazol
 Anticoagulant therapy during study period
o Bleeding disorders or coagulation disorder
o History of an Ischemic Stroke or Intracranial Bleed
o CNS Tumor
o Intracranial Vascular Abnormality
o GI Bleeding Disorder within 6 months
o Major Surgery with 30 days
o Dialysis patients
o Eligible patients were assigned in a 1:1:1 Ticagrelor 90mg BID, 60mg BID, or Placebo.
o All patients received Aspirin, between 75-150 mg.
o Patients undergoing elective, major non-cardiovascular procedures were required to
stop study drug treatment 5 days prior and advised by physician when to restart.
Primary Efficacy End Point:
o Composite of cardiovascular death, myocardial infarction, or stroke.
Secondary Efficacy End Points:
o Cardiovascular death
o Death from any cause
Exploratory Efficacy End Points:
o Myocardial infarction
o Stroke
o Death from coronary heart disease
o Composite of death from coronary heart disease, myocardial infarction, or stroke
Primary Safety End Point:
o Thrombolysis in Myocardial Infarction (TIMI) major bleeding
Statistical analyses
including power and
sample size
calculations
Enrollment & baseline
characteristics
Safety End points (Other):
o Intracranial hemorrhage
o Fatal bleeding
o Adverse Events
o A 90% power to detect a 20% reduction in relative risk with the 90 mg dose of
Ticagrelor
o 83% power was needed to detect a19% reduction in relative risk in the 60 mg dose
o Primary efficacy analysis was done on an intent-to-treat basis
o Safety analysis included all patients randomized and received at least one dose
o A P value of P = 0.05 is considered statistically significant.
o Kaplan-Meier estimates were used to express event probabilities at a cumulative
incidences of 36 months
o Cox proportional-hazards model was used to generate hazard ratios and 95% CI
RESULTS
o
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o
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o
o
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21,162 patients were initially randomized to the study
Randomization took place between October 2010 through May 2013
20,942 patients received at least one dose of study drug or placebo
Median age was 70 years old
Median time from qualifying MI was 1.7 years
53% of qualifying events were STEMI
40% of qualifying events were NSTEMI
83% of patients had history of PCI
59.4% of patients had multi-vessel coronary artery disease
32% of patients are diabetic mellitus
16% of patients had >1 myocardial infarction
23.2% of patients had a GFR < 60 mL/min
o Median duration of follow-up was 33 months
o Medication at enrollment:
 99.8% Aspirin
 92.6% Statin
 82.6% Beta-blocker
 80.4% ACE inhibitor (or ARB)
Summary of primary
and secondary
outcomes
Ticagrelor,
90 mg
(N=7050)
Outcomes
CV death,
MI, Stroke
Death CHD,
MI, Stroke
CV death or
MI
Death CHD
or MI
CV death
Death from
CHD
MI
Brief summary of
authors’ main
discussion points
Author’s conclusions
493 (7.85)
Ticagrelor
Placebo
60 mg
(N=7067)
(N=7045)
number (percent)
487 (7.77)
578 (9.04)
NNT =84
438 (6.99)
NNT = 78
445 (7.09)
535 (8.33)
424 (6.79)
422 (6.77)
497 (7.81)
350 (5.59)
360 (5.75)
429 (6.68)
182 (2.94)
174 (2.86)
210 (3.39)
97 (1.53)
106 (1.72)
132 (2.08)
275 (4.40)
285 (4.53)
338 (5.25)
Ticagrelor,
90 mg vs
Placebo
95% ci
HR = 0.85
P= 0.008
Ticagrelor,
60 mg vs
Plavebo
HR= 0.82
P= 0.002
HR= 0.85
P= 0.01
HR= 0.81
P= 0.004
HR= 0.87
P= 0.15
HR= 0.73
P= 0.02
HR= 0.81
P= 0.01
HR= 1.00
P= 0.99
HR= 0.83
P= 0.003
HR= 0.85
P= 0.01
HR= 0.84
P= 0.01
HR= 0.83
P= 0.07
HR= 0.80
P= 0.09
HR= 0.84
P= 0.03
HR=
P= 0.14
HR= 0.84
P= 0.004
Death from 326 (5.15)
289 (4.69)
326 (5.16)
any cause
Safety End Points
TIMI major
127 (2.60)
115 (2.30)
54 (1.06)
HR= 2.69
HR= 2.32
P <0.001
P <0.001
Bleeding
NNH = 65
NNH = 81
TIMI minor
66 (1.31)
55 (1.80)
18 (0.36)
HR= 4.15
HR= 3.31
P <0.001
P <0.001
Bleeding
Bleeding
122 (2.43)
105 (2.09)
37 (0.72)
HR= 3.75
HR= 3.08
P <0.001
P <0.001
Transfusion
Bleeding
453 (7.81)
354 (6.15)
86 (1.50)
HR= 5.79
HR= 4.40
P <0.001
P <0.001
D/C
Fatal/
32 (0.63)
33 (0.71)
30 (0.60)
HR= 1.22
HR= 1.20
Nonfatal
P= 0.43
P= 0.47
ICH
Adverse Events
Dyspnea
1205
987 (15.84)
383 (6.38)
HR= 3.55
HR= 2.81
P <0.001
P <0.001
(18.93)
Dyspnea
430 (6.50)
297 (4.55)
51 (0.79)
HR= 8.89
HR= 6.06
P <0.001
P <0.001
D/C
AUTHORS’ DISCUSSION & CONCLUSIONS
Ticagrelor plus low-dose aspirin showed significance in both dosing regimens in reducing
the risk of CV death, MI, or stroke, while increasing TIMI major bleeding, TIMI minor
bleeding, bleeding requiring transfusion, d/c of therapy due to bleeding. There was no
significance observed in fatal bleeding or nonfatal Intracranial hemorrhage between study
drugs and control. In addition, both doses of Ticagrelor lead to increased dyspnea. In the
DAPT trial, which compared either Clopidogrel or Prasugrel for long-term use greater than
a year, up to 30 months, also showed a significant reduction in stent thrombosis and
adverse CV and cerebrovascular events in patients who received a stent post-MI. Although
these two study’s differed in the populations studied, they showed that there is a benefit in
using a P2Y12 receptor antagonist for greater than one year.
The addition of Ticagrelor to low-dose aspirin, for dual antiplatelet therapy should be
considered in patients whom have previously experienced a MI greater than a year. The 60
mg dose may be more favorable of a choice since it had lower rates of bleeding and
Study strengths
Study limitations
Applicability to patient
care and impact on
pharmacists and/or
healthcare providers
dyspnea which lead to a lower rate of d/c of drug.
STUDENT’S DISCUSSION & CONCLUSIONS
Strengths:
1. Studied in a large population
2. The population was diverse, including people from 31 countries
3. Baseline characteristics were similar among all three groups
4. Showed a comparison between two different doses vs placebo
5. Enrolled patients that are at a higher bleeding risk compared to DAPT trial,
therefore broadening the population that may benefit from this data
Limitations:
1. Excluded patients with a need for an oral ATc
2. Enrollment was preceded with a break in treatment prior to initiation of therapy,
with a mean start time of 1.7 years from MI.
a. This break in treatment excluded a period of time which could have been
more beneficial to patients
3. The trial did not report statistical difference between the two dose forms
4. Manufacture funded
Based on the results of this study (PEGASUS-TIMI54) and similar study’s (DAPT), P2Y12
receptor antagonists definitely have a place in therapy for long-term usage post-MI. They
may not be beneficial in patients who did not tolerate the drug well during the initial 12
months of treatment, but could be recommended in patients who tolerated the drug well
and experienced no bleeding events.
TIMI Bleeding Classification
Major:
1) Any intracranial* bleeding, OR
2) Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥5
g/dL (or, when hemoglobin is not available, a fall in hematocrit of ≥15%),
OR
3) Fatal bleeding (a bleeding event that directly led to death within 7 days)
Minor: Any clinically overt sign of hemorrhage (including imaging) that is associated
with a fall in Hgb of 3 to < 5 g/dL (or, when hemoglobin is not available, a fall in
hematocrit of 9 to < 15%)