Study

Design

N

Results

Limitations

Sjöblom, Lars et al.

Management and Prognostic Features of Intracranial Hemorrhage During anticoagulation therapy. Stroke, 2001, vol 32 (1)

Retrospective chart review

PCC=23 +/- FFP +/- Vit K

FFP=18 +/- Vit K

Vita k=23

Nothing=42

Prothromplex-T 30IU/kg

Vit K (10-20mg IV)

121

1. 30-day mortality lowest in FFP (11%), Vit K (30%) and PCC (39%) and highest in No Treatment (55%)

2. Volume of IVH and ICH both independent risk factors for 30 day and 6 month mortality

3. Initial INR and treatment modality has no significant outcome on one and six month mortality

1) Retrospective and uncontrolled

2)Time of symptom onset unknown

3)No inclusion or exclusion criteria listed

4) Mean age 74

5)10 hospitals with significantly different management

6) Most studies indicate that time from onset of symptoms to anticoagulation reversal is most important goal, this study has no data on time to reversal.

Joshua N. Goldstein, et al.

Timing of FFP administration and Rapid Correction of Coagulopathy in Warfarin Related Intracranial Hemmhorhage. Stroke 2005 (2)

Retrospective chart review

Primary: Evaluate effect of time to FFP/Vit K on INR reduction within 24hrs

Secondary: Effect on dose of FFP/Vit K on INR reduction

50% pts presenting after 4 hours sx onset

69

1)Time to FFP administration is associated with sig decrease in INR within 24 hours

2) Dose of FFP and Vit K not associated with sig decrease INR within 24 hours

3) Time to Vit K not associated with sig decrease INR in 24 hours

4)No change in morbidity or mortality with INR reversal within 24 hours

1)Retrospective

2) No trauma, AVM, tumor

3) Excluded deaths within 24hrs, 38pts excluded after DNR in ER

4)Median time to presentation 4 hours; not ultra-early

5)Used GOS for detecting improved outcomes; less sensitive than NIHSS

6)No PCC included

Fredriksson K, et al.

Emergency Reversal Of Anticoagulation After Intracranial Hemorrhage. Stroke, 1992 Jul;23(7):972-7 (3)

Retrospective Chart Review of pts with ICH on OAT reversed with FFP v.s PCC

Primary: In-house outcomes assessed via “Reaction Level Scale” and follow up with modified Rankin Scale

All pts receive Vit K (10-20)

PCC=10 (26 IU/kg Preconative)

FFP=7 (8ml/kg)

17

1)INR reduced from 2.83 to 1.22 in 4.8 hours in PCC group compared to 2.97 to 1.74 in 7.4 hours in FFP group

2)PT values corrected 4.6 times faster with PPC than FFP

3)Neurologic status via RLS better in PCC group than FFP group

4)No difference between groups with modified Rankin scale

1)Retrospective

2)Small sample

3)No control

4)Some patients received surgical intervention which is not presented in data

5) FFP dose on low side

Thorsten Steiner, et al.

Intracerebelar Hemorrhage Associated with Oral Anticoagulation Therapy; Current Practice and Unresolved Questions. Stroke 2006; 37: 256-262

(4)

Review Article

1) Give 10-20 mg vitamin K IV +/- FFP +/- PCC

Review Article

Makris M, et al. Emergency

Oral Anticoagulation Reversal: The Relative Efficacy of Infusions of FFP or PCC on Correction of Coagulopathy. Thrombosis and haemostasis, 1997 Mar;77(3):477-80. (5)

Prospective Non-randomized

PCC+Vit K=29 25-50IU/kg

FFP + Vit K= 12 800ml

(BPL F9a , Prothrompex T)

Pre-INR and 15 min post factor replacement INR. Also compated various factor levels.

41

1)Treatment with PCC provided a greater return to normal INR level compared to FFP

2)INR predicts factor 9 levels in anticoagulated but not in patients reversed with FFP

3)Factor levels significantly correlate with INR’s reversed with PCC but not with FFP

4) 0/12 FFP and 14/14 PCC pts achieved INR <1.5 after factor replacement

1)FFP group had significantly greater INR compared to PCC groups

2) No control

3) Small sample sizes

4) Unequal group sizes

Hagen B. Huttner, et al.

Hematoma Growth and Outcome in Treated Neurocritical Care Patients with Incracranial Hemorrhage Related to Oral Anticoagulation Therapy Stroke, 2006 (6)

Retrospective Non-Rrandomized

31 pts (PCC+/-Vit K/FFP)

18 pts (FFP+/- Vit K)

6 pts (Vit K 5-20mg IV)

Primary: Hematoma growth and 12 month outcome via mRAS

Median time to CT 4hrs; f/u CT in 24hrs

55

1)Decrease in frequency of hematoma growth in pcc and ffp vs. vit k (19.3%, 33.3%, 50%) p<.01

2)INR reversal within 2 hours obtained more consistantly w/ PCC v.s FFP and in no pt given only Vit K (84%, 39%, 0%)

3)In subgroup analysis of PCC V.S FFP pts who reversed within 2 hours, there was no difference in frequency of hematoma growth (19% vs. 28.5%) p=.25

4)No difference in 12 month poor outcome (mRAS) between all groups: (78%, 78%, 83%) p=.86

5)Multivariate analysis shows

a. Increase INR level after 2 hours associated with hematoma growth

b. PCC associated with lack of growth

c. Age, baseline hematoma vol, and occurrence of hematoma growth are independent factors in poor outcome

1) Non-randomized

2) Uncontrolled

3) Confounding factors such as CHF for which certain pts were given PCC rather than FFP were not recorded

4) Premorbid mRAS for pts presenting with new ICH not included

5) Unknown dose and type of PCC; unknown quantity of FFP given

Park, Paul, et al.

Recombinant Activated Factor 7 for the Rapid Correction of Coagulopathy in Non-hemophilic Neurosurgical Patients, Neurosurgery. 53(1):34-39, July 2003. (7)

Retrospective Case Series

Factor 7 dose: 90/40/180 +FFP (accept 2 pts)

2 ICH (1 OAT, 1 Liver)

1 IVH+Hydro (OAT)

1 SAH+Hydro(OAT)

2 Epidural (Trauma)

3 HE with Cerebral Edema (Liver)

9

1) Rapid reversal in 8/9 pts within 20 minutes

2) No TE complications

3) No apparent dose effect

4) Only 1 pt with trauma induced coagulopathy required repeat dosing of raF7

1) Retrospective

2) All pts received FFP at first accept for 2 who received it later

3) All pts with liver disease and ½ trauma pts received raF7 doses less than OAT pts

Subramaniam S, et al.

Unexpected Post-hemorrhagic Hydrocephalus in Patients Treated with Factor 7a. Neurology, 2006 Sep 26;67(6):1096. Epub 2006 Aug 25. (8)

Case Series

Factor 7a protocol for ICH at hospital; 40ug/kg; modified Graelo Criteria for prediction of post-hemorrhagic hydrocephalus

9

1)33% in house mortality

2)5/9 pts with IVH; 2/5 died

3)4/9 pts w/o IVH; 2/4 dies

4)Of 5/9 pts with IVH+ICH who received factor 7a; 55% developed hydrocephalus with a prediction rate of <10%

5) Factor 7a is associated with hydrocephalus among pts with IVH

1)Case series

2)Used low dose Factor 7a which in large studies did not show improvement in ICH volume

3)No control group

4)Unknown clinical consequence of hydrocephalus, unk time to follow up

Sugg, R.M et al.

Myocardial Injury in

Patients with Intracerebral Hemorrhage Treated with Recombinant Factor 7a. Neurology 2006; 67 (9)

Prospective Non-Randomized Non-Blinded Controlled study

Primary: Assess incidence of MI in pts receiving factor 7a

All pts w/OAT related ICH receive Vit K, FFP, or cryoprecipitate as well as Factor 7a

Treatment=20

No treatment=110

130

1)10% MI in tx vs. 1% non-tx

2) No difference in 30 day mortality rate (tx 20% vs. no tx 31% P=0.56)

3)2/20 tx w/ MI; ½ died; 1/110 no tx w/ MI; 1/3^rd total pts had h/o CAD

1) Non-randomized, non-blinded

2) Small treatment arm overestimates adverse effects and beneficial effects

3)Incomplete serial troponin levels in non-treated patients

Ruby Anne E. Deveras, et al.

Reversal of Warfarin Induced Excessive Anticoagulation with Recombinant Human Factor 7a Concentrate. Ann Intern Med. 2002;137:884-888. (10)

Case Series, Uncontrolled

Measured PT and INR pre and post F7a infusion

13

1)INR and factor 7 levels improve after factor 7a infusion

2) Factor 2, 9, 10 activity does not improve after factor 7a

3) No thromboembolic events

1) Uncontrolled case series

2) No control

3) No statistical analysis

Stephan A. Mayer, et al.

Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage. NEJM 2005, Feb 24^th, Vol 8

(11)

Randomized Double Blinded Placebo Controlled Study

Primary: 24 hour hematoma growth

Secondary: GCS and NIHSS neurologic status; outcome measures via mRAS, Barthel index, and EGOS

CT scan within 3 hours, tx within 1 hour CT scan

Placebo= 96

Low (40)=108

Medium (80)= 92

High (160)=103

Combined

399

1)Significant reduction in percent increase of ICH compared to placebo in the High dose group p<.02

2)Sig reduction in absolute volume of ICH in High dose group compared to placebo p<.01

3)Sig decrease in Medium and High dose group for total ICH+IVH+Edema compared to placebo group p<.001

4) Sig improved survival or combined treatment arm vs. placebo at 3 months 18% vs. 29%; relative reduction in mortality of 38% p=.02

5)Absolute reduction of 16% of death or severe disability (mras) at 3 months- treatment vs. placebo; number needed to treat is 6.5

6)mras and NIHSS improved in combined arm vs. placebo at 3 months; Barthel index improved for Medium and High dose groups

7)SAE occurred in 7% of treatment arm and 2% placebo arm which was non-significant p=.12

8)SAE that led to death or disability occurred in 2% placebo and 2% treatment groups

9) 7 cardiac events occurred in tx groups; 1 stemi; 9cva’s in tx group, 2 fatal, 5 severely disabling

10) Arterial TA events occurred in 5% tx group and 0% placebo p=.01

1)Study powered to assess ICH volume reduction and not clinical outcomes

2)Confidence intervals cross 1 on a number of outcomes that are listed as significant including ICH volume

3)No CI listed for Barthel Index and NIHSS (possibly because both analyzed using Wilcoxon Rank-sum?)

4)Excludes pts with h/o TE or vasocclusive disease, preexisting disability, OATs, GCS 3-5

5)Mean ICH vol (24ml) and GCS (14) better than many previous studies

6) Use of combined treatment date vs. placebo when individual doses do not show significance

Morgenstern LB, et al.

Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology. 1998; 51: 1359-1363. (12)

Randomized Prospective Non-Blinded Non-Controlled

Primary: 6 month GOS

Secondary: Mortality, mRAS, Barthel Index 6 month

468 surgical pts

497 medical pts

965

1)No significant difference in favorable outcomes in 122 (26%) surgical patients versus 118 (24%) medical patients

2)No significant difference in 6 month mortality in surgical (36%) vs. medical (37%) patients.

1)140 (26%) of medical patients had surgical intervention but analyzed in medical group data

2)75% surgical group received craniotomy; does not give data for minimally invasive endoscopic surgery

3)Mean time to surgery was 30 hours; not early surgery

4)Excludes ICH secondary to trauma, tumor, AVM’s.

Hemphill JC III, et al. The

ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891-897

(13)

Retrospective Review

Non-traumatic ICH

Univarate and Multivariate analysis to create grading scale for 30-day mortality

Results

GCS 0-2

ICH vol (30ml) 0-1

IVH 0-1

Infratentoral 0-1

Age (80yrs) 0-1

Total 0-6

152

1)30 day mortality 45%

2)Pulse pressure, ICH location, sex, and cause of ICH were not associated with outcome

3)GCS most strongly associated with outcome

4)Endoscopic hematoma evacuation and craniotomy did not show improved outcomes

5)Age > 80yrs ICH volume were independent predictors of outcome

6) IVH showed a strong trend but not significant prediction in outcomes.

1)Retrospective, needs prospective validation

2)Dichotomize all factors accept initial GCS

3) Places emphasis on GCS being far stronger than all other factors

4) Includes IVH even though not statistically significant

6) Scores of 4 has 97% mortality, 5 100% mortality, and no pts had score of 6. Thus, 50% of scoring range places pt at 97-100% mortality

O.P.M. Teernstra, et al.

Stereotactic Treatment of Intracerebral Hematoma by Means of a Plasminogen Activator A Multicenter Randomized Controlled Trial (SICHPA); Stroke 2003 Apr;34(4):968-74. Epub 2003 Mar 20.

(14)

Prospective Randomized Controlled study

surgical=36

non-surgical=35

Primary: 6m mortality

Secondary: ICH volume reduction and modified rankin scale

71

1) 6 Month mortality Surgical 20 (56%) and nonsurgical 20 (59%); non-significant

2)Rankin Score: non-significant

3)Hematoma enlargement in 38% surgical and 60% nonsurgical (p=0.14)

4)Hematoma enlargement with neuro deterioration or death within 7 days in 35% of surgical patients, 17% non-surgical patients (p=0.18)

5)Absolute hematoma size reduction of 18ml in surgical group v.s 7ml medical group

1)Insufficient number of patients to power study

1)Stopped early due to slow patient enrollment

2)Overall showed a relative 34% reduction in hematoma volume

3)Does faster evacuation of hematoma confer benefit? 4)Does increasing doses of tpa improve outcomes?

Davis, S. M., Broderick, et al.

Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.. Neurology 66: 1175-1181 (2006) (15)

Meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up

208

1)72.9% of patients exhibited some degree of hematoma growth.

2) Factors that were associated with increased mortality and predictive of outcomes on mRAS include

a. Percentage hematoma growth p < 0.0001

b. Initial ICH volume; p = 0.003

c. GCS p = 0.003

d. IVH p=0.007

3)Gender, location, blood glucose, and blood pressure did not predict outcomes.

1) Meta-analysis

Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage.

The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. (16)

1)All patients with acute ICH should be managed in stroke units or if required and intensive care unit. Stroke units reduce mortality and increase the likelihood of good outcomes

2)Patients should have 24-72 hours from stroke onset of continuous cardiac monitoring (level C)

3)Continuous ICP monitoring should be considered in patients who require mechanical ventilation (Class IV)

4)Medical treatment for elevated ICP should be started for neurologic deterioration (Class IV)

5)Immediate antihypertensive therapy is recommended in cases of ICH combined with myocardial infarction, aortic dissection, or acute renal failure, cautiously (Class IV)

6)Medial management for elevated ICP includes glycerol, mannitol, hyper-HAES, short term hyperventilation (Class IV)

7)rFVIIa should not be used outside a phase III trial until beneficial effect is confirmed (Level B)

8)Routine blood pressure lowering is not recommended. Treatment is recommended only for the following (Class IV)

a. Known history of HTN with systolic >180 and or diastolic >105; target blood pressure should be 170/100 (or MAP of 125)

b.Patients without history of known hypertension with systolic >160 or diastolic >95; target blood pressure should be 150/90 (or MAP of 110)

c.A reduction of > 20 % should be avoided

d.All pressures should be tailored in a monitored patient to maintain a CPP > 70

9)In general, ICP monitors should be placed in (but not limited to) patients with a GCS score of <9 and all patients whose condition is thought to be deteriorating due to elevated ICP (level of evidence V)grade C recommendation).

10)Early rehabilitation is recommended in patients with neurologic deficits as with ischemic strokes (Class IV)

11)Antiplatlet treatment after ICH must be subject to risk of microvascular disease versus risk of ICH recurrence (Class IV)

12)Surgical craniotomy for deterioration in level of consciousness (GCS level between 12-9 to < or equal to 8), if the ICH is superficial (clot is subcortical and less than or equal to 1cm from the surface and does not reach the deep basal ganglia), or if is located in the cerebellum (Level C)

13)Deep hematomas do not benefit from craniotomy. Stereotactic aspiration may be considered, especially if mass effect is present (Class IV)

14)Management of AVM include: observation, embolization, surgical excision or radiotherapy. Combinations of the above may offer best results. (Class IV)

15) If patients have an impaired level of consciousness and a hematoma of 3cm or greater in diameter, consider emergent evacuation of clot with excision of AVM in same operation if possible (Class IV)

Yasaka M, et al.

Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005; 115:455-459 (17)

Prospective non-randomized non-blinded study on pts with OATS who require reversal for hemmorhagic complications or medical procedures.

6pts= 200 IU

30pts=500 IU

3pts= 1000 IU

3 pts= 1500 IU

27pts= ICH

7pts EDH

1 pts SDH

7 pts=medical/surgical treatment

PPSB-HT Nichiyaku

N=42

1)Pts receiving 500 IU (median 8.8IU/kg) with INR <5 corrected INR to below1.5 in 96% of cases within 10 minutes

2)Pts receiving 1000 and 1500 IU (18.4 and 26 IU/kg) all corrected to INR below 1.5

3) Pts receiving 200 IU (3.3IU/kg) had INR’s >1.5 after 10 minutes in 5/6.

4) 25/27 pts with ICH had no change in hematoma vol or neurologic deterioration when INR reversed with PCC and Vit K.

5) 1 pt given pcc and no vit k had below therapeutic INR next day with hematoma enlargement.

6) 10/10 pts with INR monitored at 60 minutes, 12 hours, and 24 hours had stable INR reductions after vit K and PCC administration

7) No thromboembolic events or allergic reactions noted in any pt

1) Non-randomized

2) PCC used in this study has more factor units per ml than American brands

3) No length of f/u

4) INR and number of pt’s significantly different between groups

5) Pts receiving 1000 and 1500 IU doses did not have INR > 5 though author speculates that these doses would be beneficial in pts with INR >5.

Cartmill M, et al.

Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000; 14;458-461 (20)

Prospective non-randomized study in pts with OATS related ICH comparing time and efficacy of reversal of INR in pts treated with PCC+Vit K vs. FFP+ Vit K

6pts= PCC+ VitK

6pts=FFP (4 units) + Vit K

PCC= IXa-BPL (50u/kg)

N=12

1. PCC group had mean INR of 4.86 reversed to < 1.5 in 6/6 pts within 15 minutes of infusion.

2. FFP group had mean INR of 5.32 reversed to 2.3 with only 1/6 pts having INR <1.5 15 minutes after infusion completion.

3. Mean time to clinical reversal (from time to treatment to lab confirmation of INR) was 41 minutes in PCC and 115 minutes in FFP with only 1/6 FFP pts being successfully reversed.

4. INR of all pts with PCC were <1.5 at 48hrs; no pt receiving FFP had INR< 1.5 at 48hrs

1. Non-randomized

2. Weight based dosage for PCC; no weight based dosage for FFP

3. Unknown units of each factor in BPL PCC.

4. No reports on adverse effects at PCC dosage; somewhat higher than other authors

Preston FE, et al.

Rapid reversal of oral anticoagulation with warfarin by prothrombin complex concentrate (Beriplex); efficacy and safety in 42 patients. Br Journal Haematol. 2002; 116: 619-624. (21)

Prospective non-randomized study in pts requiring emergent reversal of OAT with PCC + Vit K

(ICH=10)

PCC=Beriplex

INR Dose N

2-3.9 25 IU/KG 20

4-6 35 IU/KG 12

>6 50 IU/kg 10

N=42

1. 33/42 (79%) pts had INR <1.3 20 minutes after PCC; 9 pts had INR between 1.3-1.9.

2. 1/42 (2.3%) pts with thromboembolic stroke associated with PCC

1. Non-randomized

2. Unknown if pts with INR 1.5-1.9 given PCC

3. Unknown which patients did not reach <1.3

4. Use of INR 1.3 as marker for optimal reduction whereas most studies use 1.5

5. No listing of pretreatment INR’s in comparison to treatment failure

6. One pt with INR >6 given 35 U/kg dose per primary attending request.

7. Lower Vitamin K given (2-5mg)

Sorensen B, et al.

Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thomboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14:469-477 (19)

Prospective non-randomized non-controlled study on rafVII in pts with cns bleeding on OATS.

6pts with ICH

1 pt with spinal trauma

rafVII dose 10-40ug/kg

5 pts received Vit K

3 pts received FFP

N=7

1. 7/7 pts treated with raFVII had INR decreased to <1.5 within 10 minutes

2. No thromboembolic complications reported

1)Non-randomized, no control

2) Small sample size

3) No follow up time interval