A journal article analysis ("journal club") I composed of a notable clinical trial during an internship/Advanced Pharmacy Practice Experience (APPE) in a community pharmacy at a hospital.

1. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice, 04/14/2022
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Journal Article Analysis: PLATelet Inhibition and Patient Outcomes (PLATO)
Background
and
overview
Title: Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes: PLATelet Inhibition and Patient
Outcomes (PLATO) Trial
Author(s): Wallentin L, Becker R, Budaj A, Cannon C, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H,
Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA
Institution(s): Uppsala Clinical Research Center, Duke Clinical Research Institute, Grochowski Hospital, Thrombolysis
in Myocardial Infarction Study Group, Brigham and Women’s Hospital, AstraZeneca Research and Development, Arhus
University Hospital, Universitätsklinikum Heidelberg, Worldwide Clinical Trials U.K., INSERM Unité 698, Assistance
Publique–Hôpitaux de Paris and Université Paris 7, University of Sheffield
Journal: The New England Journal of Medicine
Funding: Study was sponsored by AstraZeneca
Journal Citation: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary
Syndromes. New England Journal of Medicine. 2009;361(11):1045-1057. doi:10.1056/nejmoa0904327
Rationale: The rationale of this clinical trial is to determine whether ticagrelor is superior to clopidogrel for the
prevention of vascular events and death in a broad population of patients presenting with an acute coronary syndrome
(ACS).
Clinical Question (PICO): In patients with an ACS, with or without ST-segment elevation, how does treatment with
ticagrelor, compared to clopidogrel, affect rates of morbidity and mortality in a six-to-twelve-month period?
Methods
Primary Objective: The primary objective of PLATO is to evaluate whether ticagrelor is superior to clopidogrel for the
prevention of vascular events (death from vascular causes, MI, or stroke) in patients with non–ST elevation (NSTEMI)
ACS or ST-elevation (STEMI) ACS.
Design: The PLATO trial is a phase III, multicenter (862 centers), randomized, double-blind, double-dummy, parallel-
group, event-driven, international (43 countries) trial of approximately 18,000 patients hospitalized because of ACS.
Patients are randomized to receive ticagrelor or clopidogrel in a 1:1 ratio using a randomization schedule blocked by site.
Randomization must take place within 24-hours of onset of the most recent cardiac ischemic symptoms and before any
planned or urgent PCI.
Population: Consisted of participants with ACS, with or without ST-segment elevation.
• Sample Size: 18,624 New Treatment: 5554 Reference treatment: 5513
• Randomization: Patients are randomized to receive ticagrelor or clopidogrel in a 1:1 ratio using a randomization
schedule blocked by site. Randomization must take place within 24-hours of onset of the most recent cardiac ischemic
symptoms and before any planned or urgent PCI.
• Demographics:
o Significant homogeneity with treatment and control groups for all baseline characteristics (e.g., age,
race/ethnicity, BMI, comorbidities, etc.)
▪ Age: 62 in both groups (median)
▪ Race/ethnicity: 91.8% Caucasian (ticagrelor) vs. 91.6% Caucasian (clopidogrel)
▪ BMI: 27 in both groups (median)
• Inclusion:
o Hospitalized for ACS (with or without ST-segment elevation) with symptom onset in the previous 24-hours
o If no ST-segment elevation, at least two of the three following criteria must have been met:
▪ ST-segment changes on electrocardiogram to indicate ischemia (T-wave inversions).
▪ Positive biomarker test (troponins) ➔ myocardial necrosis.
▪ Other various risk factors (age ≥ 60 years, history of previous myocardial infarction or coronary
artery bypass graft, coronary artery disease with stenosis of ≥ 50% in at least two vessels, previous
ischemic stroke, transient ischemic attack, carotid stenosis of at least 50% or cerebral
revascularization, diabetes mellitus, peripheral arterial disease, creatinine clearance < 60
mL/min/1.73m2
BSA).
o If ST-segment elevation, the following two inclusion criteria had to be met:
▪ Persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left
bundle-branch block.
▪ Intention to perform primary PCI.
• Exclusion:
o Any contraindication against the use of clopidogrel, fibrinolytic therapy within 24-hours before
randomization, requirement for oral anticoagulation, increased risk of bradycardia, and concurrent therapy
with a strong CYP 3A inhibitor or inducer.

2. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice, 04/14/2022
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o Dropouts:
▪ Discontinuation of the study drug (ticagrelor) because of dyspnea occurred in 0.9% of patients in
the ticagrelor group.
Statistical Analysis: Hazard ratio, confidence intervals, probability values (p-values), Kaplan-Meier curves
• Interventions: Patients were randomized to receive either ticagrelor (180 mg loading dose plus 90 mg BID
thereafter) or clopidogrel (300-600 mg loading dose plus 75 mg daily thereafter) in a double-blind, double-
dummy fashion without run-in or washout periods.
• Endpoints:
o Primary
▪ Composite of death from vascular causes, myocardial infarction, or stroke.
o Secondary
▪ Rate of myocardial infarction alone, death from vascular causes, rate of stroke alone, rate of all-
cause mortality, rate of major bleeding, rate of major bleeding not related to CABG.
• Compliance Measured: Adherence to the study drug was defined as using >80% of the medication in each period
between visits. Compliance was assessed by the site investigator.
• Monitoring: Initially, patients were to be assessed by means of Holter monitoring for 7-days after randomization,
until a repeat assessment at 1-month had been obtained for 2000 of the enrolled patients.
• Follow-Up: Outpatient visits were scheduled at 1-, 3-, 6-, 9-, and 12-months, with a safety follow-up visit 1-month
after the end of treatment. The randomized treatment was scheduled to continue for 12-months, but patients left the
study at their 6- or 9-month visit if the targeted number of 1780 primary end-point events had occurred by that time.
• Statistical Analysis: The Cox proportional hazards model was used to assess the data for the primary and secondary
endpoints. All randomized patients in the treatment groups were included in the intention-to-treat analyses. All
secondary endpoints were tested separately in a hierarchical sequence. The investigators estimated that 1780 events
would be required to achieve 90% power to detect a relative risk reduction of 13.5% in the rate of the primary
endpoint in the ticagrelor group as compared with the clopidogrel group, given an event rate of 11% in the
clopidogrel group at 12 months.

3. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice, 04/14/2022
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Results
Findings/Results:
o Premature discontinuation of the study drug (ticagrelor) was slightly more common than in the reference
(clopidogrel) group (23.4% vs. 21.5%).
o Overall adherence rate to the study drug was 82.8%.
o Median duration of exposure to the study drug was 277 days.
o Primary
▪ Composite of death from vascular causes, myocardial infarction, or stroke.
▪ Lower with ticagrelor.
▪ 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel.
▪ Hazard ratio: 0.84; 95% confidence interval [CI], 0.77 to 0.92; P < 0.001
• This means that the ticagrelor participants were 16% less likely to experience death from a
composite of these causes over time.
• Given the 95% CI, there is a 95% chance that the CI contains the true population mean for
the hazard ratio.
▪ Number Needed to Treat (NNT) = 52.6
• 52.6 patients would need to receive ticagrelor instead of clopidogrel for one additional
patient to not experience death from a composite of any of the above causes.
o Secondary
▪ Rate of myocardial infarction alone.
▪ Lower with ticagrelor.
▪ 5.8% of patients receiving ticagrelor vs. 6.9% of patients receiving clopidogrel, P = 0.005.
▪ NNT = 90.9
• 90.9 patients would need to receive ticagrelor instead of clopidogrel for one additional
patient to not experience a myocardial infarction.
o Secondary
▪ Death from vascular causes.
▪ Lower with ticagrelor.
▪ 4.0% of patients receiving ticagrelor vs. 6.9% of patients receiving clopidogrel, P = 0.001.
▪ NNT = 34.5:
• 34.5 patients would need to receive ticagrelor instead of clopidogrel for one additional
patient to not experience death from vascular causes.
o Secondary
▪ Rate of stroke alone.
▪ 1.5% of patients receiving ticagrelor vs. 1.3% of patients receiving clopidogrel, P = 0.22 ➔ not
statistically significant.
o Secondary
▪ Rate of all-cause mortality.
▪ Lower with ticagrelor.
▪ 22% relative reduction in the rate of death from any cause at 1-year.
▪ 4.5% of patients receiving ticagrelor, vs. 5.9% of patients receiving clopidogrel; P < 0.001).
▪ NNT = 71.4:
• 71.4 patients would need to receive ticagrelor instead of clopidogrel for one additional
patient to not experience death from any cause.
o Secondary
▪ Rate of major bleeding.
▪ 11.6% of patients receiving ticagrelor and 11.2% of patients receiving clopidogrel,
respectively; P = 0.43 ➔ Not statistically significant.
o Secondary
▪ Rate of major bleeding not related to CABG.
▪ Lower with ticagrelor.
▪ 4.5% of patients receiving ticagrelor vs. 3.8% of patients receiving clopidogrel, P = 0.03.
▪ NNT = 142.9
• 142.9 patients would need to receive ticagrelor instead of clopidogrel for one additional
patient to not experience major bleeding not related to CABG.

4. Paul Pasco, PHCY 4011: Advanced Community Pharmacy Practice, 04/14/2022
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Critique
Data Analysis: Analysis was performed with both double-blinding and double-dummying to treatment groups.
• Strengths:
o The study identified a relationship of overall clinical superiority when comparing ticagrelor to the
reference drug clopidogrel in both the primary (composite) and secondary (individual) endpoints.
o Very large, international sample size (N = 18,624).
o Prospective study.
o Double-blinding and double-dummying utilized to protect against the placebo effect.
• Limitations
o Significant homogeneity with the demographics of participants (e.g., age, race/ethnicity, and comorbidities)
reduces the external validity of the study.
o Intention-to-treat analysis may underestimate the effect of the treatment.
• Internal Validity:
o Given the referenced data, there appears to be consistent evidence of a causal relationship between the use of
ticagrelor and improved patient outcomes. No confounding variables (e.g., higher doses of clopidogrel
worked similarly to ticagrelor) were identified.
o The study was conducted well (e.g., large sample, double-blinded, double-dummied, conducted at more than
one site with consistent, frequent follow-up to monitor outcomes).
• External Validity:
o The large sample size and low NNT offer compelling evidence that the conclusions drawn from this study
would be applicable to a great many more people than only those who participated. However, the
homogeneity of demographic factors may weaken the applicability of some of these causal relationships in
certain populations.
Authors’ Conclusions:
In patients with ACS, with or without ST-segment elevation, treatment with ticagrelor as compared to clopidogrel
significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the
rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. The advantages of
ticagrelor were maintained regardless of:
• Using higher loading doses of clopidogrel.
• Using invasive versus noninvasive management.
The advantages shown with ticagrelor may be due to a decrease in thrombosis without an increased propensity for major
bleeding.
Recommendations:
➢ Devise a study that has three treatment arms: one for ticagrelor, one for prasugrel, and one for clopidogrel.
➢ Diversify the demographics of participants in said study. Compensate for increased overall heterogeneity from
diversified demographics by performing additional subgroup analyses.