Clinical trial NCT02285751: High "on Treatment" Platelet Reactivity in the Intensive Care Unit
Official title: High "on Treatment" Platelet Reactivity in the Intensive Care Unit
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Critical Illness
Keywords: high on treatment platelet reactivity
acetylsalicylic acid
clopidogrel
prasugrel
ticagrelor
critically ill
pharmacokinetic
pharmacodynamics
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2014-11-07
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: pharmacodynamics (Arachidonic acid induced aggregation test with multiplate electrode aggregometry)
timeFrame: on average 3 days
Secondary outcomes:
measure: Prevalence of high "on-treatment" platelet reactivity in the intensive care unit
timeFrame: maximum 2 weeks after admission
measure: Evaluation of pharmacokinetics (Serum levels of Salicylate/acetylsalicylic acid, clopidogrel-active metabolite, prasugrel-active metabolite, ticagrelor active-metabolite)
timeFrame: on average 3 days
measure: intensive care unit mortality
timeFrame: maximum 90 days
measure: comparison of hemodynamically stable vs unstable ((defined by serum lactate>2.1mmol/l, need for circulatory support)
timeFrame: maximum 3 days
measure: major bleeding (defined by TIMI-TRITON-38 criteria)
timeFrame: average of 2 weeks within inclusion
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: General Hospital
Study officials:
affiliation: Medical University of Vienna, Department of Clinical Pharmacology
name: Bernd Jilma, Ao. Univ.-Prof. Dr. med
role: PRINCIPAL_INVESTIGATOR
References: