Alpheus trial ppt
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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
![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.](https://image.slidesharecdn.com/alpheustrialppt-210526015941/85/Alpheus-trial-ppt-16-320.jpg)
Alpheus trial ppt
- 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.
- 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
Editor's Notes
- #2: Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting (ALPHEUS)
- #3: Over the past decade, the rates of associated stent thrombosis, Q-wave myocardial infarction, stroke, and death have substantially decreased, and they are now considered rare periprocedural complications. However, development of highly sensitive cardiac troponin assays has led to the documentation of frequent periprocedural myonecrosis. Although often asymptomatic, these periprocedural complications can delay hospital discharge, and have been associated with an increased risk of future major cardiac adverse events, including death. Side branch occlusion, slow coronary flow, and embolisation are potential mechanisms of atherothrombotic complications and could be reduced by more effective antiplatelet therapy than the recommended combination of aspirin and clopidogrel.
- #10: ALPHEUS trial uses the Prospective Randomized Open, Blinded Endpoint study design approach where end points are evaluated by a blinded central Clinical End point Committee (CEC).
- #11: , defined as having a baseline cardiac troponin below the upper limit of the normal or a decreasing level in case of modestly positive cardiac troponin (within the grey zone specific to each high sensitivty troponin assay or below three times the upper limit of the local laboratory normal values), Lack of chest pain within the last 24 hours and no chest pain for more than 15 minutes are requested.
- #15: The study was open label,as a full double-blind design was not possible because of budget constraints across the two European countries. However, the primary endpoint was based on the measurement of post-PCI troponin, which is not subject to interpretation or bias, and the clinical endpoints were all adjudicated in a masked fashion, in addition to reading of PCI videos at a central core laboratory and statistical analyses.
- #17: Vasodilator-stimulated phosphoprotein (VASP) measurement is the most specific approach to evaluate the extent to which P2Y12 receptors are functionally blocked by a P2Y12 antagonist The assessment of VASP phosphorylation by ELISA was performed following the instructions of the ELISA kit (CY-QUANT VASP/P2Y12). Repeated samples were analyzed or frozen and stored within 48 hours of sample collection and after activation and lysis. Fresh blood samples (50 μL) were added to a pair of freeze-proof microtubes containing PGE1 or PGE1 + ADP. Following incubation (at RT for 10 minutes) and lysis, 1 group of fresh blood samples were analyzed immediately while others were vortexed, frozen, and stored at −20°C for future testing. Frozen samples were thawed at RT before analysis. All procedures of the assay were performed directly in the 96-well strip coated with a mouse anti-human VASP monoclonal antibody. The PGE1-activated and corresponding PGE1+ADP-activated samples were loaded into the wells. A dilution buffer was also loaded as a blank. The wells were covered, incubated for 30 minutes at RT, and washed 3 times, each with 300 μL of washing solution. The specific mouse antihuman phosphorylated VASP monoclonal antibody coupled with peroxidase was immediately added. The wells were covered, incubated for 30 minutes at RT, and again washed as described above. Tetramethylbenzidine was added for color development and incubated for 5 minutes at RT. The reaction was stopped by acidification with sulfuric acid, and the absorbance of the reaction product was measured at 450 nm within 4 hours after stopping the reaction. Optical density at 450 nm (OD450 nm) was directly related to the phosphorylated VASP present in the sample after PGE1 or PGE1 + ADP activation. The PRI was calculated using optical density (cOD450 nm) in the presence of PGE1 alone or PGE1 + ADP simultaneously, as follows: PRI (%) = (OD450 nm[PGE1] - OD450 nm[PGE1 + ADP])/(OD450 nm[PGE1] - OD450 nm[blank]) × 100.
- #20: Evidence of prolonged ischemia or procedural complication is defined by a prolonged chest pain, ECG changes, or from procedure-related complications associated with reduced coronary blood flow such as coronary dissection, occlusion/thrombus of a major epicardial artery or of a side branch, disruption of collateral flow, slow flow or no-reflow, distal embolization or imaging evidence of loss of myocardium.
- #24: Assuming a total event rate (for the primary outcome) of 30% at 48 h in the clopidogrel group, we calculated that 856 patients per group (1712 total patients) were required for 80% power to detect a difference of six percentage points (20% relative difference) in the primary outcome at a two-sided α level of 5%. Assuming a dropout rate of around 10%, 950 patients per group (1900 total patients) needed to be randomly assigned. A masked sample size reassessment was done on the primary outcome after 50% of patients were included for sample size reassessment (Addplan Software release 4) and we concluded that no sample size adjustment was necessary.
- #25: 1.In cases of withdrawal of consent, only data recorded before the withdrawal were considered. The safety analysis included all patients who received at least one dose of study drug. Sensitivity analysis-A sensitivity analysis is a method to determine the robustness of trial findings by examining the extent to which results are affected by changes in methods, models, values of unmeasured variables, or assumptions.
- #27: Patient baseline characteristics were similar between the study groups, and representative of a population of patients with stable coronary disease
- #28: The main results of the masked prespecified platelet substudy in 167 patients showed that P2Y12-mediated platelet reactivity was significantly lower with ticagrelor than with clopidogrel when measured a mean of 4·1 h (SD 1·0) after the loading dose and the next day after PCI, a mean of 21·6 h (2·5) after the loading dose Our pharmacodynamic data show thatticagrelor was more potent than clopidogrel 4 h after the loading dose, with more than half of patients having high levels of P2Y12-mediated platelet reactivity in the clopidogrel group, as well as the next day after PCI, in line with previous pharmacodynamic studies in elective PCI
- #29: At 48 h, the primary composite efficacy outcome of periprocedural myocardial infarction and major myocardial injury was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group Results were consistent across the individual components of the primary outcome these results were adjusted and seen on established risk factors for periprocedural events (diabetes, renal insufficiency, left ventricular ejection fraction <40% or previous episode of heart failure, multivessel disease, the number of stents implanted, and the total stent length per patient) and the findings were unchanged (data not shown).
- #30: The main secondary outcome, comprising periprocedural myocardial infarction and any form of myocardial injury, was similar between the two groups no significant difference was observed between the study groups for all secondary efficacy outcomes at 30-day follow-up
- #33: Kaplan meier curves
- #34: The primary safety outcome (major bleeding) occurred in only one patient at 48 h and was infrequent and similar in both groups at 30 days The rate of minor bleeding was not different at 48 h but was more frequent in the ticagrelor group compared with the clopidogrel group at 30 days,
- #35: Our results are aligned with other studies in elective PCI, and we provide results of a pooled analysis of available global randomised data (ALPHEUS and SASSICAIA trials), representing 2664 stable coronary patients undergoing elective PCI and showing no benefit of stronger P2Y12 inhibition using ticagrelor or prasugrel compared with clopidogrel to decrease periprocedural complications
- #36: Our study supports the safety of elective percutaneous revascularisation, with low rates of complications. By contrast, periprocedural myonecrosis was frequent in this study, with a similar level to other studies during the past decade that have used sensitive definitions of myocadial injury and infarction and troponin as a biomarker, but could be more related to mechanical rather than thrombotic causes
- #37: 1. open-label trial with inherent biases that were controlled by the use of the prospective, randomised, open-label, blinded endpoint design, which comprised masked adjudication of all outcomes, masked measurement of troponin after PCI, and an independent masked review of all PCI videos by core laboratory expert readers.