The ALPHEUS trial compared ticagrelor to clopidogrel in reducing periprocedural myocardial injury in 1900 stable coronary patients undergoing high-risk elective PCI. Patients received a loading dose of either ticagrelor 180mg or clopidogrel 300-600mg before PCI, followed by 30 days of maintenance therapy. The primary outcome of periprocedural MI or major myocardial injury within 48 hours did not differ between groups. No differences were found in secondary outcomes including death or MI at 30 days. Ticagrelor did not increase major bleeding but was associated with more minor bleeding and dyspnea. The study concluded that higher platelet inhibition from ticagrelor did not translate to reduced per

1. JOURNAL CLUB
TOPIC- ALPHEUS TRIAL

2. BACKGROUND
 PCI is widely used in patients with stable coronary artery disease
and is considered a safe procedure with < 1% complication.
 However PCI-related MI and myocardial injury can be frequently
diagnosed after the PCI
 Studies have demonstrated that patients have a better prognosis in
the absence of such periprocedural myonecrosis
 A stronger platelet inhibition could potentially lower these events
and make the procedure safer.

3. EVIDENCE BEFORE THIS STUDY
 The P2Y 12 inhibitors prasugrel and ticagrelor provide a
higher level of platelet inhibition than clopidogrel, with
a faster onset of action and improved clinical outcomes
in patients with ACS
 These two drugs have not been well investigated in
elective percutaneous coronary intervention (PCI) for
stable coronary patients
 In 2018, European guidelines on revascularisation gave a
IIb recommendation to prasugrel and ticagrelor in
elective PCI for high-risk situations but without
supporting evidence (level of evidence C)

4.  Hard clinical events are rare after elective PCI but peri-
procedural myocardial infarction (type 4a) and
myocardial injury are frequent, especially in high-risk
situations, and have been associated with a poorer
prognosis.
 Whether ticagrelor could reduce periprocedural
myonecrosis in high-risk elective PCI is unknown.

5. STUDY OBJECTIVE
 To examine the effect of ticagrelor as compared with
clopidogrel to reduce periprocedural myocardial
necrosis in stable coronary patients undergoing
highrisk elective PCI

6. ALPHEUS TRIAL- THE HYPOTHESIS
 The investigators hypothesize that this study will show
superiority of the new P2Y12 inhibitor over clopidogrel in
elective PCI on the primary ischemic endpoint (peri-
procedural MI and myocardial injury) without significant
excess bleeding (BARC definition).
 Condition or disease - stable coronary artery disease ,
indication for PCI and
at least one high-risk characteristic
 Intervention/ treatment- Drug: Ticagrelor
Drug: Clopidogrel
 Phase - 3

7. STUDY DESIGN
 Study Type :
Interventional (Clinical Trial)
 Actual Enrollment :
1900 participants
 Allocation: Randomized
 Intervention Model:
Parallel Assignment
 Masking: None (Open
Label)
 Primary Purpose:
Treatment
Official Title: Assessment of Loading
With the P2Y12 Inhibitor Ticagrelor or
Clopidogrel to Halt Ischemic Events in
Patients Undergoing Elective Coronary
Stenting: The ALPHEUS Study
Actual Study Start Date : January
9, 2017
Actual Primary Completion Date :
May 29, 2020
Actual Study Completion Date :
September 15, 2020

8. ARMS AND INTERVENTIONS
Arm Intervention/treatment
Experimental: Ticagrelor Arm Drug: Ticagrelor
Loading dose of 180mg given after
angiography and before PCI , followed
by a 30 days treatment with the
maintenance dose of 90mg bid.
Active Comparator: Clopidogrel
Arm
Drug: Clopidogrel
Loading dose of 300 or 600mg given
after angiography and before PCI ,
followed by a 30 days treatment with
the maintenance dose of 75mg per
day.

9. METHODS
 Study organisation-
 The ALPHEUS study is a phase IIIb, international, multicenter,
controlled, randomized, open-label trial designed by the
ACTION Study Group
 Funded by the Fonds de Dotation ACTION and a grant by
AstraZeneca
 Study Chairman--Dr Silvain
 Study Scientific Director- Dr Montalescot assisted by the
steering committee responsible for the medical, scientific, and
operational conduct of the study
 50 high-volume PCI centers in 2 countries (France and
Czech Republic)

10. STUDY POPULATION
 1,900 stable coronary patients (chronic coronary syndrome)
18 years of age or older undergoing PCI with at least 1
criterion of high-risk features.
 Patients with stable coronary artery disease were eligible
for the study if they had an indication for PCI and at least one
high-risk characteristic .
 Patients who were on chronic clopidogrel treatment
(maintenance dose for more than 5 days) were eligible for the
study.
 All patients provided written informed consent.

11. INCLUSION CRITERIA
 Male or female patients aged ≥18 y
 Undergoing nonemergent single or multiple-site/vessel PCI during
the same procedure
 Negative cTn before enrollment (according to local measurement;
hsTn preferably) during hospitalization for coronary angiogram or
PCI
Or
A modestly positive hs-Tn at baseline within the gray zone of the
laboratory (or <3× the URL if the gray zone is not defined) AND
decreasing levels on the last measurement performed
 Written informed consent obtained at enrollment into the study
Written informed consent obtained at enrollment into the study

12. INCLUSION CRITERIA
 Having at least 1 high-risk feature as described below
- Age > 75 y
- Renal insufficiency (clearance below 60 mL/min calculated with Cockcroft-Gault formula)
- Diabetes mellitus
- Overweight (B N30)
- History of ACS (in the past 12 m) including unstable angina/non-STEMI and STEMI
- Left ventricular ejection fraction b40% and/or prior episode of heart failure
- Multivessel disease (2 or 3 V)
- Multiple stents needed defined as (1) more than 1 stent implanted in 1 vessel or (2) more than 2 stents in
2 or more vessels, or (3) total stent length envisioned N30 mm
- Left main stenting
- Bifurcation stenting (whatever the technique)
- ACC/AHA type B2 or C lesion
- Stenting of venous or arterial coronary graft

13. EXCLUSION CRITERIA
1. Women of child-bearing potential
2. Thrombolytic therapy within the previous 24 h
3. Undergoing primary PCI for ongoing STEMI
4. Undergoing rescue PCI after failed thrombolysis
5. Any other elective PCI scheduled within the following 30 d after the index
PCI
6. History of intracranial hemorrhage at any time
7. Increased bleeding risk: intracranial tumor or aneurysm; recent trauma or
major surgery (<1 m) (including bypass surgery); active gastrointestinal bleed,
active bleeding
8. Uncontrolled arterial hypertension (defined as a systolic BP ≥180 mm Hg
and/or diastolic BP ≥100 mm Hg)
9. Recent (<48 h) or planned spinal/epidural anesthesia or puncture
10. . Impaired hemostasis such as known INR >1.5; past or present bleeding
disorder ,thrombocytopenia (platelet count b100,000/μL)

14. ENROLLMENT AND RANDOMIZATION
 Eligible patients were randomly assigned (1:1) to either ticagrelor
or clopidogrel by use of an interactive web response system
available via the electronic case report form, and stratified by
centre.
 The primary endpoint was based on the measurement of post-
PCI troponin
 Administration of the loading dose of the study drug took place
after the angiogram and before PCI- staged or immediately after
CAG
 Random assignment could not occur before the coronary
status was known.

16. PROCEDURES
 Ticagrelor –loading 180 mg f/b 90 mg BD
 Clopidogrel – 300-600 mg loading f/b 75 mg OD
(whole or crushed form) for 30 days
 Samples were taken at baseline, 4 h after the loading dose,
and the day after PCI
 Platelet inhibition was evaluated using the vasodilator-
stimulated phosphoprotein platelet reactivity index measured
by ELISA(VASP Phosphorylation PRI)
PRI (%) = (OD450 nm[PGE1] - OD450 nm[PGE1 + ADP])/(OD450 nm[PGE1] - OD450 nm[blank]) × 100.

18. OUTCOMES
 PRIMARY
1.The pre-specified primary outcome of the trial is the rate of
PCI-related MI (type 4a or 4b) or major myocardial injury
within 48 hours (or at hospital discharge if earlier) of elective
PCI/stent.
2. MI related to early stent thrombosis (type 4b) are defined
according to the modified Academic Research Consortium
definitions (ARC definitions) with a rise and/or fall of cTn
values >URL).

20. SECONDARY OUTCOMES
 composite of death, myocardial infarction (all type), or stroke
or transient ischaemic attack
 composite of death or myocardial infarction (type 1, 4, and 5)
 composite of death, myocardial infarction (type 1, 4, and 5),
major myocardial injury, urgent revascularisation, or recurrent
ischaemia requiring catheterisation.

21. SAFETY OUTCOME
 The primary safety outcome was major bleeding, evaluated by
the Bleeding Academic Research Consortium (BARC) criteria
(BARC 3 or 5)
 Secondary safety outcomes included minor or nuisance
bleeding (BARC 1 or 2) and any bleeding (BARC 1 to 5).
 A net clinical benefit outcome comprising death, myocardial
infarction, stroke, or major bleeding was also evaluated.

22.  Bleeding risk was evaluated with the Dual Antiplatelet Therapy (DAPT) score
and the PARIS bleeding score
 In addition to the baseline level, cardiac troponin was measured 6 h and 24 h
after PCI or at discharge if this occurred earlier, and the peak values were
considered for outcome assessment. Clinical outcomes were evaluated at 48
h and 30 days.
 All angiographic or PCI videos were analysed by at least two masked
independent experts (who did not otherwise participate in the study) of the
ACTION central core laboratory.
 An independent clinical event committee whose members were unaware of
the treatment assignments reviewed all outcomes, except death.

23. STATISTICAL ANALYSIS

24. STATISTICS
 The primary analysis was based on all events that occurred in the
intention-to-treat population, defined as all patients who underwent
randomisation and PCI and who provided written informed consent.
 The primary outcome was analysed by χ 2 test.
 Prespecified subgroup analyses to evaluate variations in treatment effect
were done by logistic regression models, with terms for treatment,
subgroup, and interaction of treatment with subgroup
 Sensitivity analyses were done for primary and secondary endpoints
using multivariate mixed logistic models, including centre as a random
effect and with or without a priori known risk factors as covariables

25.  Data were collected and analysed according to the predefined
statistical analysis plan by academic statisticians of the ACTION
Study Group.
 The trial was monitored by an independent data and safety
monitoring board.
 All statistical analyses were done using SAS version 9.4 software.
 The trial was registered with ClinicalTrials.gov , NCT02617290 .

26. RESULTS

35. DISCUSSION
 Ticagrelor was not superior to clopidogrel in reducing periprocedural
myocardial infarction or myocardial injury within 48 h of high-risk PCI
in stable coronary patients or 30 days

36. LIMITATIONS
 Open label trial
 Patients under chronic clopidogrel therapy included
 All troponin assays authorized to reflect real-life PCI centres
 The trial doesn’t provide reliable information on hard clinical
outcome which are rare in elective pci

37. CONCLUSION
 Higher level of platelet inhibition obtained with ticagrelor, does
not translate into a reduction of periprocedural MI or
myocardial injury within 48 hours of high-risk PCI performed in
stable coronary patients.
 None of the clinical outcomes differed between groups at 30-
day follow-up.
 Ticagrelor use for 30 days did not translate in increased major
bleeding rate but there was an excess of minor bleeding and
dyspnea

38.  Thank you