• 
• 

Three Part Question

In [patients with AAICH (Anticoagulant Associated Intracerebral / Intracranial Hemorrhage) and elevated INR from VKA (Vitamin K Antagonist)], how useful are [PCC (Prothrombin Complex Concentrate) and rFVIIa (recombinant factor VIIa)] in [INR normalization, clinical outcome and hematoma reduction]?

Clinical Scenario

A 62 year old female school teacher who lives alone presents with a headache. She has a history of atrial fibrillation and takes Coumadin daily. You order a MDCT (Multi-detector computerized tomography) head scan and find an intracerebral hemorrhage. During her time in the ED she becomes slightly confused. What is your management?

Three Part Question:
In [patients with AAICH (Anticoagulant Associated Intracerebral / Intracranial Hemorrhage) and elevated INR from VKA (Vitamin K Antagonist)], how useful are [Vitamin K, FFP (Fresh Frozen Plasma), PCC (Prothrombin Complex Concentrate) and rFVIIa (recombinant factor VIIa)] in [INR normalization, clinical outcome and hematoma reduction]?

Search Strategy

Using PubMed (Medline 1999 to Jan 2009).
[Warfarin or Anticoagulation] and [Intracerebral or Intracranial hemorrhage]. Limits: Humans, English.

Search Outcome

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)were used to assess the article. There is a paucity of higher level evidence thus only three 2b and c studies and a single 1a study was found addressing the question.

Search Outcome: 164 papers were found; the four most relevant studies are reviewed.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Can Ilyas MD et Al. 2008 USA	Trauma patients taking VKA with ICH: Retrospective cohort-controlled database review. Review of seven years of experience. Four years without and 3 years with rFVIIa usage.	2b (Individual retrospective cohort study)	Finding	rFVIIa provides prompt correction of the INR, of dose-dependent duration, in patients with ICH intracranial hemorrhage associated with warfarin use.	Retrospective non-randomized. The inherent problems associated with the completeness of registries, selection of patients, aggressiveness of therapies including the choice of dose of rFVIIa, and decisions of families all may have been confounding variables.
Sung B. Lee, MD; Edward M. Manno, MD; et Al. 2006 USA	Retrospective chart review of 45 patients suffering from AAICH. FFP treatment measuring time to INR correction, hematoma progression and mortality rate were measured.	2c (Outcomes descriptive study)	Door to FFP administration (median)	3 hours	Retrospective chart review. This study included patients treated at outside hospitals. Ictus to treatment time thus could have been markedly variable.
			Door to FFP completion (median)	9.25 hours
			Door to INR normalization (median)	30 hours
M. Cartmill*, G. Dolan , J. L. Byrne et Al. 2000 UK	AAICH Prospective cohort study of 6 patients in PCC group compared to standard therapy group using FFP and Vitamin K measuring time to INR correction.	2b (Individual Prospective Cohort Study)	Mean INR correction time	PCC group 41 minutes The FFP / Vitamin K group 115 minutes.	Very small prospective cohort study. Limited power because of size of sample.
Kent J. DeZee, MD, MPH; William T. Shimeall, MD, MPH et Al. 2006 USA	Excessive anticoagulation: Systematic Review of RCT studies in patients with INR >4. Measurement of INR correction at 24 hours using IV, PO and SC administration.	1a (Systematic review of RCT studies)	Measurement of INR correction	Oral and IV Vitamin K showed correction of INR 80% and 77% respectively at 24 hours. SC correction was 31% at 24 hours.	The studies used variable Vitamin K dosages. A number of studies showed variable patient follow up and inadequate methodology to calculate metanalysis values.

Comment(s)

The patient that presents with AAICH whether traumatic or spontaneous presents serious challenges to the health care team. Physicians must use advanced medical and surgical decision making to facilitate the best outcomes possible. It is clear that conventional therapy with Vitamin K and FFP is painfully slow in correcting the INR. The correction of the INR is critical to surgical or observational management. Hematoma growth is directly proportional to the INR. RCT studies to date have not been adequate to provide level 1b evidence or the performance of 1a systematic reviews to ascertain patient outcome measurements.

Clinical Bottom Line

• Vitamin K should only be administered by IV or PO routes and alone does not reverse anticoagulation for many hours. It is then only is effective in 77-80% of patients because of cytochrome P450 variability.

• FFP is slow to administer and takes a median of 30 hours to correct the INR. Large volumes of fluid are necessary to administer adequate amounts. Patients are also subject to blood product hazards such as transfusion reactions, HIV and Hepatitis.

• Recombinant Factor VIIa and PCC products correct the INR rapidly without fail taking only a few minutes to INR normalization.

• Clinical outcome studies of mortality and neurological function are not robust enough to make meaningful decisions. These outcomes are possible to define using well controlled RCT studies with adequate subject numbers.

• PCC and rFVIIa products should be administered to patients suffering from AAICH to normalize the INR.

References

1. Can Ilyas MD et Al. Recombinant factor VIIa for warfarin-associated intracranial bleeding Journal of Clinical Anesthesia (2008) 20, 276–279
2. Sung B. Lee, MD; Edward M. Manno, MD; et Al. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. NEUROLOGY 2006;67:1272–1274
3. M. Cartmill*, G. Dolan, J. L. Byrne et Al. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. British Journal of Neurosurgery 2000; 14(5): 458± 46
4. Kent J. DeZee, MD, MPH; William T. Shimeall, MD, MPH et Al. Treatment of Excessive Anticoagulation With Phytonadione (Vitamin K) A Meta-analysis Arch Intern Med 2006;166:391-397