ACS - Acute Coronary Syndrome Clinical Trial
Official title:
Pharmacokinetic/Pharmacodynamic Effects of add-on Antiplatelet Therapy With Parenteral Cangrelor as Compared to Standard Dual Antiplatelet Treatment in Patients With ST-elevation Myocardial Infarction Complicated by Out-of-hospital Cardiac Arrest and Treated With Targeted Temperature Management
In patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary angioplasty (PCI) P2Y12 receptor (P2Y12r) inhibition should be achieved as soon as possible. Resuscitated STEMI-patients receiving targeted temperature management (TTM, therapeutic hypothermia) after cardiac arrest, however, show deteriorated and delayed early response to available oral P2Y12r inhibitors. Therapeutic hypothermia attenuates the drugs' effectiveness by reducing its gastrointestinal absorption and metabolic activation. Acute stent thrombosis is 5-fold increased after angioplasty following resuscitated cardiac arrest because of insufficient early platelet suppression. Thus, aggressive antiplatelet strategies are needed to achieve optimal platelet suppression during PCI in those patients. The first intravenous P2Y12r inhibitor, cangrelor, has recently received marketing authorization for the acute treatment of STEMI. We hypothesize that add-on antiplatelet therapy with intravenous Cangrelor on-top of standard dual anti platelet therapy (DAPT) with Prasugrel or Ticagrelor is superior to standard antiplatelet therapy alone in terms of suppressing ADP-dependent platelet activation in resuscitated STEMI-patients receiving TTM.
Neurologic damage after cardiac arrest is frequent and therapeutic options to improve
neurological outcome are limited. Treatment by therapeutic hypothermia (TH, 32-34◦C) for
12-24 h showed improved neurological outcome in several trials. Therefore, international
guidelines recommend targeted temperature management (TTM) to 32-34◦C (or at least 36°C) for
12-24 h, especially when the initial rhythm was ventricular fibrillation.
However, patients treated with TTM after cardiac arrest show deteriorated and delayed
response to P2Y12 receptor (P2Y12r) inhibitors as determined by platelet reactivity index
vasodilator-stimulated phosphoprotein phosphorylation (PRI VASP) after administration of the
loading dose of clopidogrel, prasugrel and ticagrelor. Especially the response to clopidogrel
is poor with up to >80% non-responder after 24 hours. Impaired P2Y12r blockade may lead to
acute stent-thrombosis and trigger overall adverse outcome.
There are several explanations for the impaired efficacy of P2Y12r inhibitors in cardiac
arrest patients. First, marketed oral P2Y12r inhibitors have to be applied in crushed form
via nasogastric tube in comatose post cardiac arrest patients. Placement of nasogastric tube
and crushing may delay onset of therapy. Second, drug uptake and bioavailability of oral
P2Y12r inhibitors are dependent on gastric motility and sufficient splanchnic blood supply,
which is affected by TTM, acute critical illness (shock) and concomitant therapy.
Particularly, sedation and analgesic agents, especially concomitant morphine therapy, can
hamper gastric emptying. Various recent trials demonstrated that morphine administration
delays and attenuates clopidogrel, prasugrel and ticagrelor exposure and action in healthy
subjects and patients with myocardial infarction.
The recently authorized parenteral cangrelor is an adenosine triphosphate (ATP) analogue that
binds reversibly and with high affinity to the platelet P2Y12r. It induces a highly effective
inhibition of ADP-induced platelet aggregation immediately after intravenous (iv) bolus
administration and allows for restoration of platelet function within 1-2 h of infusion
discontinuation. The pharmacokinetic properties known so far suggest cangrelor being the
"ideal" P2Y12r inhibitor for patients with cardiac-ischemia triggered OHCA treated with TH
and may overcome the impaired and delayed P2Y12r blockade seen with the oral P2Y12r
inhibitors.
Cardiac arrest is a leading cause of death among adults over the age of 40 in the European
Union (EU) and other western countries. In the EU alone, more than 400.000 people of all ages
experience EMS-assessed out-of-hospital non-traumatic cardiac arrest each year and most of
them die. In a large proportion of these patients (about 50%) an acute coronary syndrome
(ACS), mainly acute ST-elevation myocardial infarction, leading to ventricular fibrillation
and cardiac standstill is the cause of the cardiac arrest. Various trials demonstrated that
early cardiac intervention including stent placement to the culprit lesion improves outcome
in this patient group. The P2Y12r plays a central role in platelet activation and P2Y12r
inhibitors are part of standard care in patients with ACS. Delayed and insufficient P2Y12r
inhibition may predispose to acute stent thrombosis with potential devastating effects
including cardiogenic shock, re-arrest and death. Given the deteriorated and delayed response
to oral P2Y12r inhibitors in cardiac arrest patients treated with TH, clinical evaluation of
the recently marketed parenteral P2Y12r inhibitor cangrelor is mandatory in this patient
group.
To determine the effect of add-on cangrelor in STEMI-associated out-of-hospital cardiac
arrest (OHCA) who receive TTM and are scheduled for PCI, a phase 4 trial will be
conducted.The trial consists of 2 parts. Part A (n=12, 8months duration): An open-fashioned
pilot safety-study to ensure sufficient platelet suppression (<466AU*min, impedance
aggregometry) over 24 hours after concurrent cangrelor-prasugrel/ticagrelor administration.
The aim is to determine pharmacokinetics and -dynamics of oral P2Y12r-inhibitors with and
without concomitant administration of cangrelor. Part B (n=48, 32months duration): A
factorial randomized, placebo-controlled, double-blind study with 4 study cohorts enrolling
48 patients who will first be randomised to receive prasugrel (n=24) or ticagrelor (n=24) and
secondly to additionally receive cangrelor or placebo (sterile saline). Primary endpoint:
ADP-dependent platelet reactivity at time of stent placement (AU*min). Student's t-test to
test H0 (no difference in AU*min, cangrelor vs placebo).
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