Antiplatelet Therapy After Cardiac Arrest

• Sponsor: University Medical Centre Ljubljana (Other)
• Overall Status: Completed
• CT.gov ID: NCT02224274
• Collaborator: (none)
• Enrollment: 57
• Location: 1
• Arms: 2
• Duration (Months): 22
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

There is growing evidence that standard dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel is not as effective in the setting of therapeutic hypothermia after cardiac arrest as in normothermic patients. The reasons for this are probably slower gastrointestinal motility, absorption and liver metabolism required for clopidogrel to take action. Since ticagrelor has faster intestinal absorption and no need for liver metabolism we expect its effect to be good even in patients with therapeutic hypothermia after cardiac arrest. Patients treated with therapeutic hypothermia after cardiac arrest and percutaneous coronary intervention will be randomised into two groups. One will be treated with ASA and clopidogrel and the other with ASA and ticagrelor. Blood samples will be collected before and 2, 4, 12, 22 and 48 hours after P2Y12 inhibitor administration. Platelet function will be measured by VerifyNow P2Y12 assay and by Multiplate ADPTest. Differences between the groups will be analysed.

Hypothesis: Antiplatelet therapy with ticagrelor is more effective than therapy with clopidogrel in the comatose survivors of cardiac arrest treated with therapeutic hypothermia and percutaneous coronary intervention (PCI).

Condition or Disease	Intervention/Treatment	Phase
Cardiac Arrest; Postresuscitation Syndrome; Myocardial Infarction (ST-Elevation Myocardial Infarction and Non-ST-Elevation Myocardial Infarction)	Drug: Clopidogrel; Drug: Ticagrelor	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparison of Antiplatelet Therapy With Clopidogrel and Ticagrelor in Patients After Cardiac Arrest Treated With Therapeutic Hypothermia
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clopidogrel These patients will be treated with clopidogrel 600 mg loading and than 75 mg/24 h.	Drug: Clopidogrel; Other Names: Clopidogrel (Plavix)
Experimental: Ticagrelor These patients will be treated with ticagrelor 180 mg loading and than 90 mg/12 h.	Drug: Ticagrelor; Other Names: Ticagrelor (Brilique)

Outcome Measures

Primary Outcome Measures

1. VerifyNow P2Y12Test - Platelet Reactivity [12 h after P2Y12 inhibitor loading]

   Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.

Secondary Outcome Measures

1. VerifyNow P2Y12Test - % Inhibition [12 hours after P2Y12 inhibitor loading]

   % inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as <11% inhibition.

2. Multiplate ADP Test [12 hours after P2Y12 inhibitor loading]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female and male over 18 years old

• Unconscious survivors of cardiac arrest treated with therapeutic hypothermia

• Acute coronary syndrome (NSTEMI or STEMI) as a reason of cardiac arrest

• PCI with stent implantation

• Provision of informed consent prior to any study specific procedures is impossible because subjects are unconscious at the moment of inclusion

Exclusion Criteria:

• Use of any P2Y12 inhibitors in last 10 days

• Use of prasugrel before and 48 hours after loading dose of P2Y12 inhibitor

• Use of eptifibatide before and 48 hours after loading dose of P2Y12 inhibitor

• Thrombocytopenia (<50*109/L)

• Allergic reaction to acetylsalicylic acid, clopidogrel or ticagrelor

• Ticagrelor contraindications: previous intracranial bleeding, active pathological bleeding, moderate to severe hepatic impairment, heart rate < 40/min at presentation

• Suspected or confirmed pregnancy

• Use of bivalirudin before and 48 hours after loading dose of P2Y12 inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Medical Centre Ljubljana	Ljubljana		Slovenia	1000

Sponsors and Collaborators

• University Medical Centre Ljubljana

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos K, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Response to letter regarding article, "Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction". Circ Cardiovasc Interv. 2013 Apr;6(2):e29. doi: 10.1161/CIRCINTERVENTIONS.113.000134.
• Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63.
• Bjelland TW, Hjertner Ø, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation. 2010 Dec;81(12):1627-31. doi: 10.1016/j.resuscitation.2010.07.002. Epub 2010 Aug 19.
• Gorjup V, Radsel P, Kocjancic ST, Erzen D, Noc M. Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation. 2007 Mar;72(3):379-85. Epub 2006 Dec 11.
• Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.
• Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009 Jul;37(7 Suppl):S186-202. doi: 10.1097/CCM.0b013e3181aa5241. Review.
• Součková L, Opatřilová R, Suk P, Čundrle I Jr, Pavlík M, Zvoníček V, Hlinomaz O, Šrámek V. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol. 2013 Mar;69(3):309-17. doi: 10.1007/s00228-012-1360-0. Epub 2012 Aug 14.
• Steblovnik K, Blinc A, Bozic-Mijovski M, Kranjec I, Melkic E, Noc M. Platelet reactivity in comatose survivors of cardiac arrest undergoing percutaneous coronary intervention and hypothermia. EuroIntervention. 2015 Apr;10(12):1418-24. doi: 10.4244/EIJY14M05_02.
• Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013 Aug 17;382(9892):614-23. doi: 10.1016/S0140-6736(13)61170-8. Epub 2013 Jul 26. Erratum in: Lancet. 2014 Mar 29;383(9923):1128.

• Responsible Party: Marko Noc, Marko Noc, MD, PhD, University Medical Centre Ljubljana
• ClinicalTrials.gov Identifier: NCT02224274
• Other Study ID Numbers: Hypothermia: Clopi vs Tica
• First Posted: Aug 25, 2014
• Last Update Posted: Feb 27, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by Marko Noc, Marko Noc, MD, PhD, University Medical Centre Ljubljana: Antiplatelet Therapy; Cardiac Arrest; Therapeutic hypothermia; Myocardial infarction (ST-Elevation Myocardial Infarction and Non-ST-Elevation Myocardial Infarction)
• Additional relevant MeSH terms: Myocardial Infarction; Heart Arrest; ST Elevation Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Infarction; Clopidogrel; Ticagrelor

Study Results

Participant Flow

Recruitment Details	Recruitment from August 2014 to May 2016 at UMC Ljubljana, Slovenia, Europe
Pre-assignment Detail	Reasons for exclusion were intraprocedural eptifibatide/thrombolysis (11), decision of attending physician (8) and bradycardia (1)

Arm/Group Title	Clopidogrel	Ticagrelor
Arm/Group Description	These patients will be treated with clopidogrel 600 mg loading and than 75 mg/24 h. Clopidogrel	These patients will be treated with ticagrelor 180 mg loading and than 90 mg/12 h. Ticagrelor
Period Title: Overall Study
STARTED	17	20
COMPLETED	16	20
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Clopidogrel	Ticagrelor	Total
Arm/Group Description	These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.	These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.	Total of all reporting groups
Overall Participants	16	20	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64 (9)	61 (12)	62 (11)
Sex: Female, Male (Count of Participants)
Female	3 18.8%	3 15%	6 16.7%
Male	13 81.3%	17 85%	30 83.3%
ST-Elevation Myocardial Infarction in postresuscitation ECG (Count of Participants)
Count of Participants [Participants]	12 75%	16 80%	28 77.8%

Outcome Measures

1. Primary Outcome

Title	VerifyNow P2Y12Test - Platelet Reactivity
Description	Platelet reactivity reflects P2Y12 inhibitor effect. Higher values mean normal platelet reactivity due to low P2Y12 inhibition response, while lower values mean decreased platelet reactivity due to the effect of a P2Y12 inhibitor. High on-treatment platelet reactivity was defined as >208 PRU.
Time Frame	12 h after P2Y12 inhibitor loading

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clopidogrel	Ticagrelor
Arm/Group Description	These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.	These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.
Measure Participants	16	20
Mean (Standard Deviation) [PRU]	238 (67)	101 (75)

2. Secondary Outcome

Title	VerifyNow P2Y12Test - % Inhibition
Description	% inhibition reflects P2Y12 inhibitor effect regarding basal platelet reactivity (defined as: (1- (platelet reactivity/basal platelet reactivity)) x 100). Higher values mean better P2Y12 inhibition response. High on-treatment platelet reactivity was defined as <11% inhibition.
Time Frame	12 hours after P2Y12 inhibitor loading

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clopidogrel	Ticagrelor
Arm/Group Description	These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.	These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.
Measure Participants	16	20
Mean (Standard Deviation) [% inhibition]	4 (11)	55 (32)

3. Secondary Outcome

Title	Multiplate ADP Test
Description	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.
Time Frame	12 hours after P2Y12 inhibitor loading

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clopidogrel	Ticagrelor
Arm/Group Description	These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.	These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.
Measure Participants	16	20
Mean (Standard Deviation) [U]	28 (17)	15 (10)

Adverse Events

Time Frame	From the date of randomization until hospital discharge or death during hospitalization.
Arm/Group Title	Clopidogrel		Ticagrelor
Arm/Group Description	These patients were treated with clopidogrel 600 mg loading and than 75 mg/24 h.		These patients were treated with ticagrelor 180 mg loading and than 90 mg/12 h.
All Cause Mortality
	Clopidogrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)		9/20 (45%)
Serious Adverse Events
	Clopidogrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)		9/20 (45%)
Cardiac disorders
Death	7/16 (43.8%)	7	9/20 (45%)	9
Nervous system disorders
Cerebrovascular insult	1/16 (6.3%)	1	1/20 (5%)	1
Surgical and medical procedures
Bleeding Academic Research Consortium (BARC) 3a and 5	2/16 (12.5%)	2	3/20 (15%)	3
Stent thrombosis	1/16 (6.3%)	1	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Clopidogrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/16 (62.5%)		10/20 (50%)
Blood and lymphatic system disorders
Minor bleeding	2/16 (12.5%)	2	1/20 (5%)	1
Cardiac disorders
Bradycardia/asystoly	0/16 (0%)	0	1/20 (5%)	1
Ventricular tachycardia	0/16 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration Pneumonia	8/16 (50%)	8	7/20 (35%)	7
Vascular disorders
Arterial embolism	1/16 (6.3%)	1	0/20 (0%)	0

Limitations/Caveats

Did not address effectiveness of prasugrel. Not powered to address stent thrombosis or bleeding.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.