Acute Myocardial Infarction, Cardiogenic Shock
Conditions
Keywords
Acute myocardial infarction, Cardiogenic shock, Primary percutaneous coronary intervention, Dual antiplatelet therapy, Cangrelor, Ticagrelor
Brief summary
Multicenter, international, randomized, placebo-controlled, double-blind trial comparing intravenous cangrelor and crushed oral ticagrelor in patients with acute myocardial infarction complicated by initial cardiogenic shock (CS-AMI) and treated with primary angioplasty (PCI). The Dual Antiplatelet Therapy For Shock Patients With Acute Myocardial Infarction (DAPT-SHOCK-AMI) trial tests the hypothesis that intravenous cangrelor is (a) more effective in terms of its rate of onset and the proportion of patients achieving effective periprocedural inhibition of ADP-induced platelet aggregation and (b) at least as effective as the recommended treatment of oral (crushed) ticagrelor in reducing major cardiovascular events in patients with initial CS-AMI indicated for primary PCI strategy.
Detailed description
Randomization to study drugs will be performed using an online database system for data collection. After entering basic patient data, the assigned arm and the randomization code will be generated based on a predefined randomization scheme. Concomitant therapy includes acetylsalicylic acid: an initial intravenous dose of 500 mg, followed by a daily oral dose of 100 mg. A proton pump inhibitor is also recommended. Additional therapies, such as further antithrombotic treatments (e.g., GP IIb/IIIa inhibitors, heparin) and mechanical support (IABP, ECMO), remain fully within the competence of the treating physician. Electronic database - eCRF. The data from individual follow-up assessments will be entered into an electronic database. The online instrument CLADE-IS will be used for data collection; this instrument provides robust options for electronic case report form (eCRF) design, hierarchical administration of user rights and a user-friendly web interface. The system provides predefined validation rules, conversions of variables, and it considers the relationships between variables; user access is controlled by the hierarchical system of user rights and user roles, and database operations are stored for audits and tracking of changes. Data safety is ensured through physical security of the servers, authorized access, and backup procedures. Laboratory collections. The efficacy of the antiplatelet drugs cangrelor and ticagrelor will be determined using flow cytometry analysis of intracellular VASP (vasodilator-stimulated phosphoprotein) phosphorylation. Study Committees: Executive c., Steering c., Endpoint adjudication c., Data safety monitoring board. Monitoring. External monitor Clinical Research Associate (CRA) Definitions. Death is defined as death from all causes. Death from cardiovascular causes is defined as a death with evidence of a cardiovascular cause or any death without clear evidence of a non-cardiovascular cause. All deaths are considered cardiac unless a clear non-cardiac cause can be identified. Any unexpected death (for example, in patients with a co-existing, potentially fatal non-cardiac disease such as cancer or infection) is classified as a death from cardiovascular causes. Myocardial reinfarction (MI) is defined as a new (additional) MI that must differ from the MI based on which the patient was enrolled into the study, satisfying the universal definition of MI criteria. Urgent revascularization of the infarct-related artery is defined as a new emergent/urgent revascularization of the artery that was intervened in during the initial procedure due to repeated manifestations of ischemia after the completion of the initial PCI. Stroke is defined as the rapid onset of a new neurological deficit due to an ischemic or hemorrhagic lesion in the central nervous system, with symptoms lasting at least 24 hours from their onset or resulting in death. Definitive stent thrombosis is defined according to the Academic Research Consortium criteria. New heart failure is defined as a hospitalization or emergency check-up for heart failure in a doctor's office or emergency room that requires treatment. Bleeding is defined according to the Bleeding Academic Research Consortium (BARC) criteria. External collaborating centre for data-management and statistical analyses: Institute of Biostatistics and Analyses at the Faculty of Medicine of the Masaryk University in Brno, Czech Republic.
Interventions
DRUGCangrelor
Cangrelor: IV bolus 30 µg/kg (application \< 1 minute) followed immediately by continuous infusion at 4 µg/kg. Tables to calculate bolus dose in ml and infusion (in ml per hour) rate for each body weight group will be prepared in advance and will be included in the study medication kit to accelerate treatment start. * Cangrelor treatment will be discontinued after circulatory stabilization (but no earlier than 2 hours after infusion initiation) i.e. after systolic Blood Pressure (sBP) is maintained at the level \> 100 mmHg for one hour after the end of IABK and/or vasoactive treatment is discontinued, but no later than 4 hours after PCI, * 30 minutes before the end of Cangrelor infusion, administration of Ticagrelor 180 mg (crushed tablets) and then dose 90 mg every 12 hours.
DRUGTicagrelor
Ticagrelor: 180 mg loading dose - crushed tablets, 2 x 90 mg maintenance dose
Sponsors
Charles University, Czech Republic
Masaryk University
Ministry of Health, Czech Republic
National Institute for Metabolic and Cardiovascular Disease Research
Institute of Hematology and Blood Transfusion, Czech Republic
BioVendor LM
Faculty Hospital Kralovske Vinohrady
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age over 18 years 2. Acute myocardial infarction according to the definition of ESC/ACC/AHA, indicated for emergency percutaneous coronary intervention (primary PCI strategy) 3. Cardiogenic shock present upon admission due to the AMI (≥ 2 of the criteria below are satisfied) 1. sBP \< 90 mmHg with the absence of hypovolemia 2. Need of vasopressor and/or inotropic therapy 3. Presence of the signs of the organ hypoperfusion - cyanosis, cold acra, disorder of consciousness, congestive heart failure 4. Informed consent form signed 5. Women of childbearing potential should be protected from pregnancy throughout the study (relevant for long-term use of ticagrelor). Suitable methods of contraception in this case include hormonal contraceptives, barrier methods, or complete withdrawal - as long as it is consistent with the patient's lifestyle.
Exclusion criteria
1. Contraindications of antiplatelet therapy with ticagrelor/cangrelor * Recent (\< 6 months) major bleeding * Recent (\< 1 month) major surgery/injury * History of intracranial bleeding * History of stroke/TIA * Known intolerance to ticagrelor/cangrelor * Severe impairment of hepatic function * Concomitant administration of strong CYP3A4 inhibitors (for example, ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) 2. Administration of a loading dose of an oral P2Y12 inhibitor prior to admission (clopidogrel ≥ 300 mg, ticagrelor 180 mg, prasugrel 60 mg) 3. Need of concomitant chronic anticoagulation therapy due to indications such as atrial fibrillation, artificial valve, thromboembolic disease, etc.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Laboratory endpoint | At the end of primary percutaneous coronary intervention; Within 24 hours from randomization | The periprocedural rate of onset and the proportion of patients who achieve effective\* P2Y12 platelet receptor inhibition defined by a Platelet Reactivity Index (PRI) value. \*PRI less than 50% as measured by the vasodilator-stimulated phosphoprotein phosphorylation flow cytometric assay |
| Primary Clinical Endpoint | Within 30 days after randomization | The composite of all-cause death, myocardial infarction, or ischemic stroke expressed as a proportion of patients with any of these events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key secondary safety endpoint | Within 30 days and one year after randomization | Bleeding as defined by BARC type ≥ 3B, expressed as a proportion of patients with this event. |
| Secondary net-clinical endpoint | Within 30 days and one year after randomization | Death, myocardial infarction, urgent revascularization of the infarct-related artery, stroke, or major bleeding as defined by the BARC type ≥ 3B criteria expressed as a proportion of patients with any of these events. |
| Secondary efficacy endpoint | Within 30 days and one year after randomization | Cardiovascular death, myocardial infarction, urgent revascularization, and heart failure expressed as a proportion of patients with any of these events. |
| Secondary endpoint | Within 30 days and one year after randomization | Heart failure, expressed as a proportion of patients with this event. |
| Other secondary outcome | Within 30 days and one year after randomization | Individual components of the primary clinical endpoint. |
| Key secondary efficacy endpoint | Within 30 days and one year after randomization | Death, myocardial infarction, urgent revascularization of the infarct-related artery, stent thrombosis, or ischemic stroke expressed as a proportion of patients with any of these events |
| Secondary safety endpoint | Within 30 days after randomization | Bleeding as defined by BARC type ≥ 3B, expressed as a proportion of patients with this event. |
| Secondary laboratory endpoint | 1 hour after primary PCI | Effective\* P2Y12 platelet receptor inhibition defined by Platelet Reactivity Index (PRI) value \*PRI less than 50% as measured by the vasodilator-stimulated phosphoprotein phosphorylation flow cytometric assay |
| Secondary outcome | From randomization to the end of vasoactive pharmacotherapy / mechanical circulatory support, within 30 days after randomization | Duration of vasoactive pharmacotherapy and/or mechanical circulatory support in days |
| Other secondary efficacy endpoint | Within 30 days and one year after randomization | Death from cardiovascular causes, expressed as a proportion of patients with this event. |
| Other secondary endpoint | Within 30 days after randomization | Definite stent thrombosis, expressed as a proportion of patients with this event. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cost analysis | Within 30 day and one year after randomization | Cost-effectiveness analysis |
| MRI sub-study endpoints | Within one year after randomization | Magnetic Resonance Imaging sub-study |
| Echo sub-study endpoints | Within one year after randomization | Echocardiographic substudy |
Countries
Czechia, France, Germany, Poland, Slovakia
Outcome results
None listed