Clinical trial NCT00928915: International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage
Official title: Multicenter, Prospective Randomized Trial on the Use of Prothrombin Complex and Fresh Frozen Plasma in Patients With Intracerebral Hemorrhage Related to Vitamin K Antagonists
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Intracranial Hemorrhages
Keywords: Intracranial Hemorrhages
Vitamin-K antagonist
Hemostatic treatment
Prothrombin complex
Fresh frozen plasma
Intracranial Hemorrhages related to vitamin-K antagonist
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2009-06-26
Enrollment: 54
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: Intracerebral haemorrhage (ICH) is the most feared complication in patients on vitamin K antagonists (VKA). VKA related ICH occurs 8-10 times more frequently and the mortality is 2 times higher than in non-anticoagulated patients. Mortality may rise up to 67%. The higher mortality rate may in part be due to the higher rate of haematoma expansion (HE) over a longer period after symptom onset. International guidelines recommend treatment of VKA-ICH with prothrombin complex (PCC) or fresh-frozen plasma (FFP) both in combination with Vitamin-K. But these recommendations are not based on randomized controlled trials. It is known that these drugs lower the INR, and thus it is assumed that normalization of coagulopathy may lead to haemostasis and reduction of HE. Safety and efficacy of these treatments have never been studied in a prospective controlled trial.

The investigators' questions are: How potent are PCC and FFP in normalization of the INR? What is the safety profile of each of these drugs?


Eligibility criteria: Inclusion Criteria:

* Spontaneous ICH (intraparenchymal), subdural hematoma (SDH) diagnosed by CT scanning ≤ 12 hours after onset of symptoms. In case of unknown time of symptom onset: time between last seen in healthy condition and first CCT ≤ 12 hours.
* Therapy receiving vitamin K antagonists (VKA)
* International Normalized Ratio (INR) ≥ 2
* Signed informed consent form, or signed informed consent by a legal representative, judicial consent in cases where no legal representative is available in time, or consent of an independent physician familiar with the indication in cases where the first three possibilities can not be realized.

Exclusion Criteria:

* Patients with ICH not related to vitamin-K antagonist therapy or
* Patients with secondary ICH related to infarction, hemophilia or other coagulopathy, tumor, hemorrhagic infarction, cerebrovenous thrombosis, aneurysm, arteriovenous malformations (AVM) or severe trauma
* Deep Coma (GCS ≤ 5) at the time of admission or before intubation if intubated outside the hospital
* Known previous disability (mRS \> 2 before stroke occurred)
* Acute myocardial ischemia, acute septicemia, acute crush injury, any history of acute hemorrhagic disseminated intravascular coagulation, acute thrombotic stroke
* Known history of intermittent claudication
* Known recent thrombotic event \< 30 days
* Acute or known congestive heart failure (NYHA III, IV)
* Pulmonary edema
* Known liver failure (child-pugh-score C)
* Known alcohol or other drug abuse
* Known active malignant disease
* Known thrombocytopenia (platelets \<50,000/µL), hemorrhagic diathesis (primary defects of coagulation, fibrinolysis, platelets)
* History of hypersensitivity to the investigational products or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational product
* Known allergy to heparin or history of heparin induced thrombocytopenia.
* Pregnancy and lactation
* Concomitant use of antithrombotic (with PTT \> 1.5 of normal PTT), thrombolytic treatment.
* Use of aspirin, clopidogrel or dipyridamole or combinations thereof (e.g. Aggrenox®) is not an exclusion criterion. These drugs should be discontinued and not restarted earlier than 24 hours after normalization of INR if indicated.
* Previous participation in this trial

Primary outcomes:
measure: INR ≤ 1.2 within 3 hours after start of drug infusion
timeFrame: 3 hours
Secondary outcomes:
measure: Safety: Number of thromboembolic events
timeFrame: 90 days
measure: Efficacy: Percentage of volume increase
timeFrame: 24 hours
measure: Clinical outcome
timeFrame: day 90
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Heidelberg University Clinic
Study officials:
affiliation: Department of Neurology, Heidelberg University Hospital Germany
name: Thorsten Steiner, MR, PhD, MME
role: PRINCIPAL_INVESTIGATOR
References:
citation: Steiner T, Griebe M, Ivandic B, et al. Multicenter, prospective randomized trial on the use of prothrombin complex and fresh frozen plasma to normalize the INR in patients with coumadine related intracerebral hemorrhage related to vitamin K antagonists - The INCH-trial. Cerebovascular Disease 2009;27:185
citation: Steiner T, Freiberger A, Griebe M, Husing J, Ivandic B, Kollmar R, Pfefferkorn T, Wartenberg KE, Weimar C, Hennerici M, Poli S. International normalised ratio normalisation in patients with coumarin-related intracranial haemorrhages--the INCH trial: a randomised controlled multicentre trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex--study design and protocol. Int J Stroke. 2011 Jun;6(3):271-7. doi: 10.1111/j.1747-4949.2010.00560.x. Epub 2011 Jan 10.
citation: Steiner T, Poli S, Griebe M, Husing J, Hajda J, Freiberger A, Bendszus M, Bosel J, Christensen H, Dohmen C, Hennerici M, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016 May;15(6):566-73. doi: 10.1016/S1474-4422(16)00110-1. Epub 2016 Apr 11.