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Cangrelor in Comatose Survivors of OHCA Undergoing Primary PCI

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ClinicalTrials.gov Identifier: NCT04005729
Recruitment Status : Recruiting
First Posted : July 2, 2019
Last Update Posted : January 14, 2020
Sponsor:
Collaborator:
Chiesi Slovenija, d.o.o.
Information provided by (Responsible Party):
Marko Noc, University Medical Centre Ljubljana

Tracking Information
First Submitted Date  ICMJE April 1, 2019
First Posted Date  ICMJE July 2, 2019
Last Update Posted Date January 14, 2020
Actual Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
  • VerifyNow P2Y12Test - Platelet Reactivity [ Time Frame: 1 hour after the start of cangrelor infusion/1 hour after the start of PPCI in controls ]
    Platelet inhibition measured by VerifyNow as P2Y12 reaction units (PRU). Platelet reactivity reflects P2Y12 inhibitor effect with higher PRU values showing low P2Y12 response and lower values decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.
  • VerifyNow P2Y12Test - Platelet Reactivity [ Time Frame: 3 hours after the start of cangrelor infusion/3 hours after the start of PPCI in controls ]
    Platelet inhibition measured by VerifyNow as P2Y12 reaction units (PRU). Platelet reactivity reflects P2Y12 inhibitor effect with higher PRU values showing low P2Y12 response and lower values decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.
  • VerifyNow P2Y12Test - Platelet Reactivity [ Time Frame: 5 hours after the start of cangrelor infusion/5 hours after the start of PPCI in controls ]
    Platelet inhibition measured by VerifyNow as P2Y12 reaction units (PRU). Platelet reactivity reflects P2Y12 inhibitor effect with higher PRU values showing low P2Y12 response and lower values decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.
  • Multiplate ADP test [ Time Frame: 1 hour after the start of cangrelor infusion/1 hour after the start of PPCI in controls ]
    Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets. High on-treatment platelet reactivity was defined as >46 U.
  • Multiplate ADP test [ Time Frame: 3 hours after the start of cangrelor infusion/3 hours after the start of PPCI in controls ]
    Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets. High on-treatment platelet reactivity was defined as >46 U.
  • Multiplate ADP test [ Time Frame: 5 hours after the start of cangrelor infusion/5 hours after the start of PPCI in controls ]
    Platelet activation by adenosine diphosphate (ADP) expressed in arbitrary aggregation units (U). P2Y12 inhibitors block ADP receptors and decrease platelet activation by ADP. Higher values mean less effect of P2Y12 inhibitors, lower values mean more effect of P2Y12 inhibitors on platelets. High on-treatment platelet reactivity was defined as >46 U.
  • BARC score or the need for discontinuation of cangrelor infusion [ Time Frame: During the cangrelor infusion and up to 5 hours after the PCI ]
    Standardized bleeding definition as described by Bleeding Academic Research Consortium (BARC). Type 0: no bleeding.
    1. actionable bleeding, does not require treatment by attending physician.
    2. any overt, actionable sign of hemorrhage plus at least one criteria: (1) requiring nonsurgical, medical intervention, (2) leading to increased level of care, or (3) prompting evaluation.
    3. overt bleeding plus (1) haemoglobin drop of more than 3 g/dL or need for transfusion, (2) cardiac tamponade, (3) requiring surgical intervention, (4) intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal), (5) intraocular bleed compromising vision.
    4. CABG-related bleeding (not applicable).
    5. Fatal bleeding: (1) probable - clinically suspicious, (2) definite - overt bleeding or autopsy or imaging confirmation.
    Significant bleeding will be defined as BARC 2, 3 and 5 or the need for discontinuation of cangrelor infusion.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
  • Angiographic result - final TIMI flow [ Time Frame: Angiography review within 24 hours of P-PCI (the following day) ]
    Final angiographic result as evaluated by independent blinded interventional cardiologist. Defined as thrombolysis in myocardial infarction (TIMI) flow at the end of the procedure. TIMI 0 flow - absence of any antegrade flow beyond a coronary occlusion TIMI 1 flow - faint antegrade coronary flow beyond the occlusion, with incomplete filling of the distal coronary bed TIMI 2 flow - delayed or sluggish antegrade flow with complete filling of the distal territory TIMI 3 flow - normal flow filling the distal coronary bed completely Residual thrombus or peripheral embolization will also be noted.
  • Rate of stent thrombosis [ Time Frame: During index patient hospitalization (at discharge from the hospital, up to 30 days) ]
    Probable or definitive stent thrombosis according to Academic Research Consortium classification (ARC) of stent thrombosis. Definite stent thrombosis - confirmed at angiography or autopsy. Probable stent thrombosis - unexplained death within 30 days after P-PCI or new myocardial infarction in P-PCI vessel territory.
  • Timing of stent thrombosis [ Time Frame: During index patient hospitalization (at discharge from the hospital, up to 30 days) ]
    Probable or definitive stent thrombosis according to Academic Research Consortium classification (ARC) of stent thrombosis based on timing of events. Acute stent thrombosis 0-24 hours after stent implantation Subacute stent thrombosis 24 hours to 30 days after stent implantation
  • Survival [ Time Frame: During index hospitalization (at discharge from the hospital, up to 90 days) ]
    Survival to discharge from hospital.
  • Survival (CPC) [ Time Frame: During index hospitalization (at discharge from the hospital, up to 90 days) ]
    Survival to discharge from hospital defined as Cerebral performance category (CPC). CPC 1 - good cerebral performance (normal life). Conscious, alert, able to work and lead a normal life. CPC 2 - moderate cerebral disability (disabled but independent) CPC 3 - severe cerebral disability (conscious but disabled and dependent) CPC 4 - coma or vegetative state (unconscious) CPC 5 - brain death
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cangrelor in Comatose Survivors of OHCA Undergoing Primary PCI
Official Title  ICMJE Platelet Inhibition With Cangrelor in Comatose Survivors of Out-of-hospital Cardiac Arrest Undergoing Primary Percutaneous Coronary Intervention
Brief Summary The main objective of the trial is to find out if 4-hour continuous infusion of parenteral P2Y12 inhibitor cangrelor at the start of primary percutaneous coronary intervention (PCI) immediately and effectively suppresses platelet activity in comatose survivors of out-of-hospital cardiac arrest (OHCA). Half of the participants will receive the standard care of dual antiplatelet therapy - acetysalicylic acid and ticagrelor tablets via nasogastric or orogastric tube and the other half the standard care with additional cangrelor infusion at the start of the PCI.
Detailed Description

Coronary artery disease is an important cause of out-of hospital cardiac arrest (OHCA) and around 80 % of patients after OHCA are comatose. Considering patient's history, details concerning OHCA and ECG changes the decision on urgent cardiac catheterization is made. In case of significant coronary artery stenosis/occlusion on primary percutaneous coronary intervention stent implantation is usually needed. Dual antiplatelet therapy is the cornerstone of stent thrombosis prevention. Patients who are comatose after the return of spontaneous circulation (ROSC) differ from conscious survivors of OHCA because they are not able to take antiplatelet drugs, such as P2Y12 inhibitors, orally. Due to the need for nasogastric/ orogastric tube insertion there is a significant delay until optimal antiplatelet effect is achieved. Furthermore, there are other factors that have an impact on the pharmacokinetics of P2Y12 inhibitors, such as therapeutic hypothermia, gastroparesis, gastrointestinal tract hypoperfusion and platelet hyperreactivity because of systemic inflammatory response syndrome. These characteristics make acute and subacute stent thrombosis more common in comatose OHCA survivors leading to increased morbidity and mortality.

Heparin is the primary anticoagulant drug for comatose patients after OHCA. Antiplatelet therapy consists of intravenous aspirin and P2Y12 inhibitor. Ticagrelor is the most potent of the latter. It is available only as a tablet, which has to be crushed and dissolved and then given via nasogastric or orogastric tube. A recent study by Steblovnik et al. has shown there is an approximately 4-hour gap of inadequate platelet inhibition in comatose OHCA even if the most potent P2Y12 inhibitor ticagrelor is used. Prueller made a retrospective study assessing the addition of intravenous P2Y12 inhibitor cangrelor as a bridge of this gap to standard care. The results showed there is a significant antiplatelet effect when using cangrelor with no added bleeding risk. After literature review no prospective randomised study has been done comparing cangrelor-bridge to standard care with dual antiplatelet therapy (aspirin and ticagrelor).

The investigator's study is a single-blinded, prospective randomised study taking place at University Medical Centre Ljubljana. Thirty comatose survivors of OHCA will be randomised at the start of primary PCI into a test and control group. The control group will receive standard care with intravenous aspirin and dissolved ticagrelor tablets given via enteral tube. The test group patients will receive an additional P2Y12 bridging therapy: a bolus of cangrelor at the start of the PCI (30 mcg/kg) followed by a continuous 4-hour infusion (4 mcg/kg/min). Heparin will be used as per guidelines for a target ACT of 250-300 seconds at the time of PCI. Interventional cardiologist will decide on the use of eptifibatide (GP IIb/IIIa antagonist). Therapeutic hypothermia will be started in the catheterisation laboratory. All patients will be transferred to ICU after the procedure and level of platelet inhibition will be tested 1, 3 and 5 hours after the start of cangrelor infusion with VerifyNow and Multiplate systems. In the control group blood will be drawn at the same time intervals. Further management of patients in both arms will be no different from regular care.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Out-Of-Hospital Cardiac Arrest
  • Acute Coronary Syndrome
Intervention  ICMJE Drug: Cangrelor 50 MG
30 mcg/kg bolus, then 4h infusion 4 mcg/kg/min
Other Name: Kengrexal 50 mg
Study Arms  ICMJE
  • Experimental: Cangrelor + Ticagrelor
    Bolus of cangrelor (30 mcg/kg) and immediately afterwards a continuous intravenous infusion of 4 mcg/kg/min at the start of the primary percutaneous coronary intervention. Crushed and dissolved ticagrelor tablets (180 mg) will be given via inserted enteral tube.
    Intervention: Drug: Cangrelor 50 MG
  • No Intervention: Ticagrelor
    Crushed and dissolved ticagrelor tablets (180 mg) will be given via enteral tube (standard care).
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 1, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • age 18 to 70 years
  • comatose survivors of out-of-hospital cardiac arrest undergoing primary percutaneous coronary intervention
  • treatment with induced therapeutic hypothermia
  • no contraindication for dual antiplatelet therapy

Exclusion Criteria:

  • pregnancy
  • patients without return of spontaneous circulation or patients on ECMO
  • history of recent P2Y12 use (last 7 days)
  • history of recent vitamin K antagonist or NOAC use (last 14 days)
  • active bleeding
  • history of transient ischemic attack or cerebral vascular insult
  • strong bleeding tendency (Child C liver cirrhosis, stage IV-V chronic renal disease)
  • history of allergic reactions to acetylsalicylic acid, heparin or P2Y12 inhibitors
  • terminal disease or life expectancy less than 1 year
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marko Noc, MD PhD 0038615222296 marko.noc@mf.uni-lj.si
Contact: Peter Kordis, MD pkordis@gmail.com
Listed Location Countries  ICMJE Slovenia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04005729
Other Study ID Numbers  ICMJE KOIIM-2019-1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Marko Noc, University Medical Centre Ljubljana
Study Sponsor  ICMJE University Medical Centre Ljubljana
Collaborators  ICMJE Chiesi Slovenija, d.o.o.
Investigators  ICMJE
Principal Investigator: Marko Noc, MD PhD University Medical Centre Ljubljana
PRS Account University Medical Centre Ljubljana
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP