High "on Treatment" Platelet Reactivity in the Intensive Care Unit

High "on treatment" platelet reactivity is defined as a poor pharmacodynamic response to the administration of acetylsalicylic acid or clopidogrel. acetylsalicylic acid and clopidogrel are drugs commonly used to reduce platelet activity and prevent cardiovascular events. High "on treatment" platelet reactivity is associated with a higher cardiovascular event rate.

Ticagrelor and prasugrel, like clopidogrel both P2Y12 inhibitors are effective in treating patients with High "on treatment" platelet reactivity to clopidogrel.

Critically ill patients are a unique population with altered pharmacokinetic and pharmacodynamic properties. Gastrointestinal dysmotility with associated altered resorption and impaired microvascular function occur frequently in critically ill patients and may lead to altered resorption of orally administered drugs.

The investigators will test a minimum of 100 patients treated with 100mg acetylsalicylic acid per os and 100 patients treated with 75mg clopidogrel per os to calculate the prevalence of high "on treatment" platelet reactivity.

30 patients with high "on treatment" platelet reactivity to acetylsalicylic acid will be randomized to three new treatment groups. In the first group patients will receive 200mg acetylsalicylic acid per os, in the second group 100mg acetylsalicylic acid intravenously and in the third group 81mg chewable acetylsalicylic acid. Each group will contain 10 patients. Pharmacokinetics and pharmacodynamics will be reassessed to evaluate the new treatment.

36 patients with high "on treatment" platelet reactivity to clopidogrel will be randomized to receive either an additional loading dose of 600mg clopidogrel (n=24) or to continue normal treatment as a control group (n=12). Pharmacokinetics and pharmacodynamics will be reassessed and those patients, who are tested again to have high "on treatment" platelet reactivity in spite of the additional loading dose, will now be randomized to receive either ticagrelor or prasugrel. The investigators expect about six patients per group. The twelve patients in the control group will continue normal treatment (75mg/day) until the end of the study. Pharmacokinetics and pharmacodynamics of ticagrelor and prasugrel will be assessed. Any patient, who is tested again with high "on treatment" platelet reactivity in spite of receiving prasugrel or ticagrelor, will be finally switched to the opposite drug and a final high "on treatment" platelet reactivity testing will be conducted.

16 patients who are treated with 10mg prasugrel per os will be tested for HTPR and if positively tested will be switched to 2x90mg ticagrelor per os per day. Platelet reactivity will be reassessed to test whether switching the medication benefits the patients.

Study Overview

• Status: Unknown
• Conditions: Critical Illness
• Intervention / Treatment: Drug: clopidogrel; Drug: acetylsalicylic acid; Drug: ticagrelor; Drug: prasugrel

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bernd Jilma, Ao. Univ.-Prof. Dr. med.; Phone Number: 2981 0043140400; Email: bernd.jilma@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • General Hospital
    • Contact: Bernd Jilma, Ao. Univ.-Prof. Dr. med; Phone Number: 2981 0140400; Email: bernd.jilma@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• >18years of age
• admittance to an intensive care unit

Exclusion Criteria:

• recent surgery
• active bleeding
• known coagulation disorders
• discretion of the physician
• terminal illness (anticipated life expectancy < 3months; e.g. due to cancer)
• pregnancy
• <20000 platelets

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 200mg acetylsalicylic acid per os; patients with high "on treatment" platelet reactivity to acetylsalicylic acid are randomized to 3 different groups, one group receives 200mg acetylsalicylic acid per os	Drug: acetylsalicylic acid; Other Names: 100mg Thrombo-ASS; 200mg Thrombo-ASS; 81mg chewable aspirin; 100mg intravenous acetylsalicylic acid
Experimental: 100mg acetylsalicylic acid intravenous; patients with high "on treatment" platelet reactivity to acetylsalicylic acid are randomized to 3 different groups, one group receives 100mg acetylsalicylic acid intravenously.	Drug: acetylsalicylic acid; Other Names: 100mg Thrombo-ASS; 200mg Thrombo-ASS; 81mg chewable aspirin; 100mg intravenous acetylsalicylic acid
Experimental: 81 mg chewable acetylsalicylic acid; patients with high "on treatment" platelet reactivity to acetylsalicylic acid are randomized to 3 different groups, one group receives 81mg chewable acetylsalicylic acid	Drug: acetylsalicylic acid; Other Names: 100mg Thrombo-ASS; 200mg Thrombo-ASS; 81mg chewable aspirin; 100mg intravenous acetylsalicylic acid
Active Comparator: 75mg clopidogrel; control group for patients with high "on treatment" platelet reactivity to clopidogrel patients continue with standard treatment 75mg clopidogrel/day	Drug: clopidogrel; Other Names: 75mg po clopidogrel; 600mg po clopidogrel (loading dose)
Experimental: 60mg prasugrel; Loading dose of prasugrel for patients who remain tested with high "on treatment" platelet reactivity in spite of having received an additional loading dose of 600mg clopidogrel	Drug: prasugrel; Other Names: 60mg prasugrel per os loading dose; 10mg prasugrel per os daily
Experimental: 600mg clopidogrel; additional loading dose for 24 patients tested with high "on treatment" platelet reactivity to clopidogrel	Drug: clopidogrel; Other Names: 75mg po clopidogrel; 600mg po clopidogrel (loading dose)
Experimental: 180mg ticagrelor; Loading dose of ticagrelor for patients who remain tested with high "on treatment" platelet reactivity in spite of having received an additional loading dose of 600mg clopidogrel Loading dose of ticagrelor for patients who remain tested with high "on treatment" platelet reactivity after being treated with 10mg prasugrel daily	Drug: ticagrelor; Other Names: 180mg ticagrelor per os (loading dose)
Active Comparator: prasugrel 10mg; patients treated with 10mg prasugrel daily	Drug: prasugrel; Other Names: 60mg prasugrel per os loading dose; 10mg prasugrel per os daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pharmacodynamics (Arachidonic acid induced aggregation test with multiplate electrode aggregometry)	Arachidonic acid induced aggregation test with multiplate electrode aggregometry of patients with high "on treatment" platelet reactivity to acetylsalicylic acid after receiving new treatments as explained. adenosine diphosphate induced aggregation tested with multiplate electrode aggregometry of patients with high "on treatment" platelet reactivity to clopidogrel after an additional loading dose clopidogrel, or after receiving prasugrel or ticagrelor	on average 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of high "on-treatment" platelet reactivity in the intensive care unit	percentage of patients tested with high "on treatment" platelet reactivity according to defined values	maximum 2 weeks after admission
Evaluation of pharmacokinetics (Serum levels of Salicylate/acetylsalicylic acid, clopidogrel-active metabolite, prasugrel-active metabolite, ticagrelor active-metabolite)	Serum levels of Salicylate/acetylsalicylic acid, clopidogrel-active metabolite, prasugrel-active metabolite, ticagrelor active-metabolite	on average 3 days
intensive care unit mortality	discharge of ICU	maximum 90 days
comparison of hemodynamically stable vs unstable ((defined by serum lactate>2.1mmol/l, need for circulatory support)	hemodynamically stable vs unstable (defined by serum lactate>2.1mmol/l, need for circulatory support)	maximum 3 days
major bleeding (defined by TIMI-TRITON-38 criteria)	assessment of major bleeding incidences defined by TIMI-TRITON-38 criteria	average of 2 weeks within inclusion

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Bernd Jilma, Ao. Univ.-Prof. Dr. med, Medical University of Vienna, Department of Clinical Pharmacology

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: October 24, 2012
• First Submitted That Met QC Criteria: November 6, 2014
• First Posted (Estimate): November 7, 2014

Study Record Updates

• Last Update Posted (Actual): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 18, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: prasugrel; ticagrelor; pharmacokinetic; critically ill; clopidogrel; pharmacodynamics; acetylsalicylic acid; high on treatment platelet reactivity
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor; Clopidogrel; Prasugrel Hydrochloride
• Other Study ID Numbers: HTPR-ICU; 2012-002226-76 (EudraCT Number)