Clinical trial NCT04005729: Cangrelor in Comatose Survivors of OHCA Undergoing Primary PCI
Official title: Platelet Inhibition With Cangrelor in Comatose Survivors of Out-of-hospital Cardiac Arrest Undergoing Primary Percutaneous Coronary Intervention
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Out-Of-Hospital Cardiac Arrest
Acute Coronary Syndrome
Keywords: cangrelor
P2Y12
out-of-hospital cardiac arrest
induced hypothermia
primary percutaneous coronary intervention
Lead sponsor: University Medical Centre Ljubljana
Sponsor class: OTHER
Collaborators: name: Chiesi Slovenija, d.o.o.
First posted: 2019-07-02
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: VerifyNow P2Y12Test - Platelet Reactivity
timeFrame: 1 hour after the start of cangrelor infusion/1 hour after the start of PPCI in controls
measure: VerifyNow P2Y12Test - Platelet Reactivity
timeFrame: 3 hours after the start of cangrelor infusion/3 hours after the start of PPCI in controls
measure: VerifyNow P2Y12Test - Platelet Reactivity
timeFrame: 5 hours after the start of cangrelor infusion/5 hours after the start of PPCI in controls
measure: Multiplate ADP test
timeFrame: 1 hour after the start of cangrelor infusion/1 hour after the start of PPCI in controls
measure: Multiplate ADP test
timeFrame: 3 hours after the start of cangrelor infusion/3 hours after the start of PPCI in controls
measure: Multiplate ADP test
timeFrame: 5 hours after the start of cangrelor infusion/5 hours after the start of PPCI in controls
measure: BARC score or the need for discontinuation of cangrelor infusion
timeFrame: During the cangrelor infusion and up to 5 hours after the PCI
Secondary outcomes:
measure: Angiographic result - final TIMI flow
timeFrame: Angiography review within 24 hours of P-PCI (the following day)
measure: Rate of stent thrombosis
timeFrame: During index patient hospitalization (at discharge from the hospital, up to 30 days)
measure: Timing of stent thrombosis
timeFrame: During index patient hospitalization (at discharge from the hospital, up to 30 days)
measure: Survival
timeFrame: During index hospitalization (at discharge from the hospital, up to 90 days)
measure: Survival (CPC)
timeFrame: During index hospitalization (at discharge from the hospital, up to 90 days)
Other outcomes:
Locations:
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
Study officials:
affiliation: University Medical Centre Ljubljana
name: Marko Noc, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Radsel P, Knafelj R, Kocjancic S, Noc M. Angiographic characteristics of coronary disease and postresuscitation electrocardiograms in patients with aborted cardiac arrest outside a hospital. Am J Cardiol. 2011 Sep 1;108(5):634-8. doi: 10.1016/j.amjcard.2011.04.008. Epub 2011 Jun 14.
citation: Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018 Jan 7;39(2):119-177. doi: 10.1093/eurheartj/ehx393. No abstract available.
citation: Hogberg C, Erlinge D, Braun OO. Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment. Thromb J. 2009 Feb 23;7:2. doi: 10.1186/1477-9560-7-2.
citation: Steblovnik K, Blinc A, Mijovski MB, Fister M, Mikuz U, Noc M. Ticagrelor Versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia: A Randomized Study. Circulation. 2016 Dec 20;134(25):2128-2130. doi: 10.1161/CIRCULATIONAHA.116.024872. No abstract available.
citation: Llitjos JF, Sideris G, Voicu S, Bal Dit Sollier C, Deye N, Megarbane B, Drouet L, Henry P, Dillinger JG. Impaired biological response to aspirin in therapeutic hypothermia comatose patients resuscitated from out-of-hospital cardiac arrest. Resuscitation. 2016 Aug;105:16-21. doi: 10.1016/j.resuscitation.2016.04.027. Epub 2016 May 17.
citation: Pruller F, Bis L, Milke OL, Fruhwald F, Patzold S, Altmanninger-Sock S, Siller-Matula J, von Lewinski F, Ablasser K, Sacherer M, von Lewinski D. Cangrelor Induces More Potent Platelet Inhibition without Increasing Bleeding in Resuscitated Patients. J Clin Med. 2018 Nov 15;7(11):442. doi: 10.3390/jcm7110442.
citation: Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.
citation: Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007 May 1;115(17):2344-51. doi: 10.1161/CIRCULATIONAHA.106.685313.