International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage (INCH)

• ClinicalTrials.gov Identifier: NCT00928915
• Recruitment Status: Completed
• First Posted: June 26, 2009
• Last Update Posted: October 26, 2016
• Sponsor: Heidelberg University
• Information provided by (Responsible Party): Thorsten Steiner, Heidelberg University

Study Description

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?

Condition or disease	Intervention/treatment	Phase
Intracranial Hemorrhages	Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP)	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: July 2009
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: January 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Prothrombin complex concentrate (PCC); intravenously, 30 IU/kg	Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP); intravenous, repeated until INR ≤ 1.2
Experimental: Fresh frozen plasma (FFP); intravenously, 20ml/kg	Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP); intravenous, repeated until INR ≤ 1.2

Outcome Measures

Primary Outcome Measures :

1. INR ≤ 1.2 within 3 hours after start of drug infusion [ Time Frame: 3 hours ]

Secondary Outcome Measures :

1. Safety: Number of thromboembolic events [ Time Frame: 90 days ]
2. Efficacy: Percentage of volume increase [ Time Frame: 24 hours ]
3. Clinical outcome [ Time Frame: day 90 ]

Eligibility Criteria

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

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

Contacts and Locations

Locations

Germany

Heidelberg University Clinic

Heidelberg, Germany, 69120

Sponsors and Collaborators

Heidelberg University

Investigators

• Principal Investigator: Thorsten Steiner, MR, PhD, MME; Department of Neurology, Heidelberg University Hospital Germany

More Information

Publications of Results:

Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, Bendszus M, Bösel 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.

Other Publications:

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

Steiner T, Freiberger A, Griebe M, Hüsing 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.

• Responsible Party: Thorsten Steiner, Prof. Dr., Heidelberg University
• ClinicalTrials.gov Identifier: NCT00928915 History of Changes
• Other Study ID Numbers: AFmu-344/2008; EUDRAT 2008-005653-37
• First Posted: June 26, 2009
• Last Update Posted: October 26, 2016
• Last Verified: October 2016

Keywords provided by Thorsten Steiner, Heidelberg University:

Intracranial Hemorrhages; Vitamin-K antagonist; Hemostatic treatment; Prothrombin complex; Fresh frozen plasma; Intracranial Hemorrhages related to vitamin-K antagonist

Additional relevant MeSH terms:

Vitamins; Vitamin K; Cerebral Hemorrhage; Intracranial Hemorrhages; Hemorrhage; Pathologic Processes; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Thrombin; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Antifibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Hemostatics; Coagulants