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APPENDIX 3 - EVIDENTIARY TABLES

Vitamin-K Antagonists

First author, year

Design

Subjects

Condition

Drug reversed

Intervention therapy

Outcomes / Results/Limitations

Brody, D, 2005

Retrospective cohort

27

ICH

warfarin

rFVIIa

rFVIIa with FFP decreases INR correction time. Less FFP needed in rFVIIa group. Caution in using repeated doses rFVIIa in patients with peripheral vascular disease.

Liotta, E, 2012

Retrospective case series

928

ICH

warfarin

3+ units FFP or rFVIIa

Early reversal decreased INR more effectively, with a better discharge outcome

Safaoui, M. N., 2009

Retrospective Case series

28

Other

warfarin

PCC

INR was corrected significantly in both early PCC & late PCC groups, early PCC group saw better INR correction

Siddiq, F, 2008

Retrospective Cohort

19

ICH

warfarin

PCC

INR was corrected in both groups, rate of correction was sig faster with PCC

Boulis, N, 1999


13

ICH

warfarin

FFP vs. FFP plus PCC

Time to correction (normalization of INR) 1/3 less in PCC group. Volume FFP 399 +/- 271mL in PCC group compared to standard FFP treatment group 2712 +/- 346mL.

Sorensen, B., 2003


7

Other

warfarin

rFVIIa

INR corrected after rFVIIa, coagulation parameters improved

Brown, C. V.l, 2012


23

TBI

warfarin

rFVIIa,

Patients receiving rFVIIa at outlying hospital had lower INRs than those that did not, P=0.002

Wojcik, C, 2009


141

Other

warfarin

FEIBA

INR correction to < 1.4 was faster with FEIBA use than FFP; reversal INR was lower with FEIBA; 7% of patients receiving FEIBA had adverse events

Ivascu, F, 2005

Prospective Cohort

82

TBI

warfarin

FFP

Study evaluated previously established protocol. Reversal in 4 hours seems to have more favorable outcomes.

Ivascu, F, 2006


35

TBI

warfarin

Pre/post implementation of a rapid triage warfarin protocol

Rapid triage protocol had no effect on INR reversal or mortality

Lee, S, 2006


45

ICH

warfarin

FFP

FFP incompletely reversed INR after warfarin use, delayed time to administration completion, 12 patients had hematoma expansion prior to completion of FFP infusion

Menzin, J, 2012


414

ICH

warfarin

FFP

FFP incompletely reversed INR after warfarin use

Menzin, J, 2012


405

ICH

warfarin

FFP

FFP inconsistently reversed INR after warfarin use (67% remained uncorrected after 1 day); patients who remained uncorrected had a higher risk of mortality

Jaffe, J., 2009

Prospective case series

86

ICH

warfarin

FFP or PCC in 14 patients with coagulopathy

Strong and independent relationship of patient age, GCS score and ICH volume on mortality and functional outcome

Lin, J., 2003


4

EDH(1), SDH(3)

warfarin

FFP, rFVIIa

INR reversed effectively. 1 death, one good outcome, 2 excellent outcomes

Amin, A, 2012


12

SDH

warfarin

FFP, Vit K

Interruptions in anticoagulation up to 3 weeks pose minimal risk with patients with mechanical heart valves

Bair, H, 2005


76

ICH

warfarin

FFP, Vit K

Mortality decreased from 48% to 10% after protocol

Chou, S, 2012

Retrospective Registry cohort

89

ICH

warfarin

FFP, vit k, rFVIIa

rFVIIa group had lower INR at hours 3 and 6 and received fewer units of FFP. SSD higher survival with surgical hemotoma evacuation compared to standard therapy cohort.

Goldstein, J, 2006


69

ICH

warfarin

FFP/Vit K

Early time to treatment did not improve outcomes

Khorsand, N, 2011


67

ICH

warfarin

Fixed dose PCC

Target INR reached equally in both groups, good clinical outcome similarly good in both groups

Bobbitt, L, 2011

Prospective Cohort

173

Other

warfarin

PCC

4.6% patients had definite or probable thrombotic event and 3.5% had a probable thrombotic event with elevated troponins

Cabral, K, 2012


30

ICH

warfarin

PCC

Standardized warfarin reversal protocol employing 3 factor PCC, FFP, Vit K resulted in rapid and sustained reversal of INR with moderate incidence of anticipated adverse events.

Dowlatshahi, D, 2012

Prospective Registry

141

ICH

warfarin

PCC

Shorter onset to treatment time did not have a positive effect on clinical outcome.

Hanger, H, 2012


88

ICH

warfarin

PCC

early administration of PCC improved survival but not functional outcome

Huttner, H. B., 2006


55

ICH

warfarin

PCC

PCC associated with reduced incidence and extent of hematoma growth compared to FFP and Vit K

Imberti, D, 2011

Prospective Case series

46

ICH

warfarin

PCC

PCCs are effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with ICH.

Joseph, B, 2013


85

ICH

warfarin

PCC

INR reduction similar, but possibly decreased use of other blood products needed in PCC group; cost lower in PCC group

Kalina, M, 2008


111

TBI

warfarin

PCC

INR reversal was better and time to OR more favorable in PCC cohort

Kuwashiro, T, 2011


50

ICH

warfarin

PCC

ICH progression, poor outcome, & mortality were lower in PCC patients, but not statistically significant; multivariate logistic regression suggests PCC associated with a reduction in poor outcome (mRS < 3)

Lorenz, R, 2007

Prospective Cohort

8

ICH

phenprocoumon

PCC

Quick correction of INR by PCC (10min) + repletion of clotting factors, good effectiveness as judged by investigators

Rizos, T, 2010

Prospective Cohort

26

ICH

warfarin

PCC

POC monitoring was comparable to clinical lab monitoring of INR & PCC reversal

Sarode, R, 2013

Prospective, Randomized, Controlled, multicenter, Phase 3b

202

Life-threatening hemorrhage (12% with intracranial hemorrhage)

warfarin

PCC vs. FFP

Significantly faster INR correction 1.3 with 4-factor PCC (Kcentra) versus FFP. Similar hemostatic efficacy and no difference in adverse events. Fluid overload more common with FFP

Goldstein, JN 2015

Prospective, Randomized, Controlled, multicenter, Phase 3b

181

Patients requiring urgent surgery or invasive procedures (2 patients with cranial neurosurgery)

warfarin

PCC vs. FFP

Significantly faster INR correction 1.3 and superior hemostasis with 4-factor PCC (Kcentra) versus FFP. No difference in adverse events. Fluid overload more common with FFP

Frontera, JA

2014


64

Intracranial Hemorrhage (SAH, SDH, IPH)

warfarin

PCC vs. FFP vs. PCC+FFP

Significantly improved adjusted 3-month modified Rankin scores in patients who received 3-factor PCC compared to FFP. No difference in PCC alone or PCC+FFP. PCC associated with less major hemorrhage compared to FFP.

Parry-Jones, 2015

Retrospective, multicenter, registry study

1547

ICH

warfarin

PCC vs. FFP vs. PCC+FFP vs. no reversal

Highest adjusted mortality rates for no reversal (62%), followed by FFP (46%), PCC (37%) and PCC+FFP (28%).

Switzer, J, 2012


70

ICH

warfarin

PCC

INR correction to < 1.4 was 63%, higher baseline INR decreased likelihood of correction, + FFP had no impact

Yasaka, M, 2002


17

Other

warfarin

PCC

PCC + Vit K significantly decreased INR, plasma levels of coagulant factors increased immediately after administration; PCC alone decreased INR initially, but came back up 12-24hr later; Vit K didn't significantly change INR until 12-24hr after

Sarode, R, 2012


11

ICH

warfarin

PCC + rFVIIa

INR was corrected consistently, time to dosing was faster than FFP

Makris, M., 1997


41

Other

warfarin

PCC + Vit K

PCC & FFP reversed INR elevations due to warfarin, PCC predicts INR response

Toth, P, 2012


131

ICH

warfarin

PCC + Vit K

Prolonged time to PCC in most patients, shorter in ICH; Vit K also prolonged

Mohrien, K, 2014


35

1

warfarin

PCC + Vit K

INR correction occurred in 85.7% of patients receiving 3fPCC (median time to INR reversal was 48 minutes)

Lankiewicz, M, 2006


58

Other

warfarin

PCC +/- FFP

INR reversal was not different with or without FFP; PCC generally effective, 4 thromboses seen

Wozniak, A, 2012


150

Other

warfarin

PCC +/- Vit K

Octaplex significantly decreased INR, maintained for up to 30hr; hemostasis in 57% of non-CNS patients, 50% hemostasis in CNS patients; Vit K given to 107 patients. Of note, dosing is not well reported & unclear how that impacted the results

Yasaka, M, 2004


42

2,5,7

warfarin

PCC +/- Vit K

PCC + Vit K significantly decreased INR, other procoagulant factors increased immediately after administration; PCC alone decreased INR initially, but came back up 12-24hr later; Vit K did not significantly change INR until 12-24hr after

Chapman, S, 2011


31

trauma

warfarin

PCC, FFP, VitK

PCC when added to FFP and Vit K resulted in a more rapid time to reversal of the INR

Bellal, J, 2012


85

TBI

warfarin

PCC, rFVIIa

PCC is safe and effective in treating coagulopathy in TBI while reducing costs and resource use

Fredriksson, K, 1992


17

ICH

warfarin

PCC, vit K

PCC/Vit K reversed INRs sooner than FFP/Vit K

Freeman, W, 2004

Prospective Case series

7

ICH

warfarin

rFVIIa

2 deaths, 5 discharged with severe neurologic deficits with GCS 3

Ilyas, C, 2008


54

ICH

warfarin

rFVIIa

Patients treated with rFVIIa corrected INRs to 1.3 and remained corrected for 12.2 +/- 8.8 hours

Nishijima, D, 2010


40

TBI

warfarin

rFVIIa

No difference in mortality or discharge disposition, trend towards more VTE in rFVIIa group, INR correction better with rFVIIa

Pinner, N, 2010


11

Other

warfarin

rFVIIa

INR correction better with rFVIIa than PCC

Robinson, M, 2010


101

Other

warfarin

rFVIIa

12.8% had new thrombosis (10 DVT, 3 CVA) over 90 days after rFVIIa; no association with receipt of rFVIIa dose

Woo, C, 2012


63

ICH

warfarin

rFVIIa

Reversal with rFVIIa & PCC was sig faster vs FFP, rFVIIa had rebound in INR within 48hr; rash, DIC, pulmonary edema reported

Baker, J, 2006

Prospective Cohort

223

N/A

warfarin

Vit K

reduction in INR next day

Kawamata, T, 1995


27

Other

warfarin

Vit K

Thrombosis off OAC is rare, good recovery is typical after holding or reversing warfarin

Berwaerts, J, 2000


272

ICH

warfarin

Vit K, FFP, Factor IX,

proportion of patients who die from OAC ICH is more than double the number of ICH not OAC related

Direct Factor Xa Inhibitors

Author, year

Design

Subjects

Condition

Drug reversed


Outcome/Results/Limitations

Wang et al, 2013

Randomized, cross-over study

18

Healthy subjects

Apixaban

20 mg (single dose)

Activated charcoal (50 g) 2 hr and 6 hr post-dose

Activated charcoal administered 2 or 6 hr after apixaban dose reduced its T1/2 (from 13,4 hr to 5.3 and 4.9 hr) and AUC (exposure reduced by 50% and 28%)

Escolar et al 2014

Ex-vivo study

10

Healthy subjects (plasma donors)

Apixaban added to plasma to reach 200 ng/mL (twice the concentration achieved with 5 mg twice daily)

4F-PCC (Beriplex) to simulate plasma concentrations achieved by 50 U/Kg

aPCC (FEIBA) to simulate plasma concentrations achieved by 75 U/Kg

rFVIIa to simulate plasma concentrations achieved by 270 mcg/Kg

CT corrected better by rFVIIa, followed by aPCC and PCC, but results were heterogeneous (PCCs better on TG tests and rFVIIa better on TEM).

rFVIIa restored levels of platelet deposition.

Eerenberg et al, 2011

Randomized, placebo-controlled, cross-over study

12

Healthy subjects

Rivaroxaban

20 mg twice daily for 2.5 days

4F-PCC (Cofact)

50 U/kg

PT completely normalized by 4F-PCC and ETP and normalization sustained for 24 hours

Marlu et al, 2012

Randomized cross-over study

10

Healthy subjects

Rivaroxaban

20 mg (single dose)

4F-PCC (Kanokad) 0.25, 0.5, and 1 U/mL;

aPCC (FEIBA) 0.25, 0.5, 1, and 2 U/mL;

rFVIIa

0.5, 1.5 and 3 mcg/mL

FEIBA corrected all parameters; 4F-PCC and rFVIIa only corrected some.

Perzborn et al, 2014

Ex-vivo study


Rivaroxaban (added to plasma to simulate maximal concentration achieved with 20 mg/d)

4F-PCC (Beriplex) to simulate plasma concentrations achieved by 25 and 50 U/Kg

aPCC (FEIBA) to simulate plasma concentrations achieved by 50 U/Kg

rFVIIa to simulate plasma concentrations achieved by 270 mcg/Kg

aPCC and rFVIIa were more effective than PCC in reversing prolongations of PT, CT, and TG lag time, but no agent achieved better than 50% normalization. ETP was strongly reversed by aPCC, and less so by PCC.

Dinkelaar et al, 2013

Ex-vivo study


Rivaroxaban (added to plasma to reach up to 800 mcg/L)

4F-PCC (Cofact) to simulate concentration rates used to correct VKA

PCC did not normalize PT or TG lag time, but did normalize ETP.

Herrmann et al 2014

Ex-vivo study

15


Rivaroxaban (10 mg/d)

3F-PCC (Prothrobinex)

aPCC (FEIBA)

rFVIIa

(all added to achieve plasma concentrations used to correct VKA)

TG parameters were significantly corrected by PCC and aPCC, but less so by rFVIIa

Korber et al 2014

Ex-vivo study


Rivaroxaban (added to plasma to)

4F-PCC (Octaplex) to simulate plasma concentrations achieved by 25 and 50 U/Kg

rFVIIa to simulate 90 and 180 mcg/Kg

rFVIIa reversed PT prolongation and improved TEM parameters, but PCC did not.

Zahir et al, 2015

Randomized, double-blind, placebo-controlled, cross-over study evaluating bleeding after punch biopsy

110

Healthy subjects

Edoxaban

60 mg (single dose)

4F-PCC

50, 25, 10 U/kg

Dose dependent reversal of bleeding time and endogenous thrombin potential with 4F-PCC (complete reversal with the 50 U/kg dose).

Partial reversal of PT and improvement in bleeding volume with 50 U/kg.

Halim et al, 2014

Ex-vivo study

6


Edoxaban (plasma concentration 150 and 300 ng/ml)

rFVIIa

0.8 and 1.8 mg/ml

aPCC (FEIBA) 0.75 and 1.5 U/ml

rFVIIa and aPCC reduced but did not correct PT, aPTT and anti-FXa activity

Ansell et al,

2014

Randomized, double-blind, placebo-controlled

80

Healthy subjects

Edoxaban

60 mg (single dose)

PER977

5 to 300 mg IV

Single dose of 100 to 300 mg of PER977 corrected the whole blood clotting time within 10 minutes and for 24 hours.

Mean fibrin-fiber diameter was restored to normal within 30 minutes of PER977 administration

Zhou et al, 2013

Animal model of ICH (by collagenase injection). Placebo-controlled study

378

Mice

Rivaroxaban

3, 10, or 30 mg/kg

4F-PCC (Beriplex) 25, 50, and 100 u/Kg; FFP 200 mcL; and rFVIIa 1mg/kg

4F PCC, FFP, and rFVIIa prevented excess hematoma expansion induced by rivaroxaban. Effect of PCC was dose-dependent. None normalized the PT, but rFVIIa reduced it. Variable effects on coagulation factors.

Perzborn et al, 2013

Animal models of bleeding (rats: injury to mesenteric artery branch; baboons: skin incision). Placebo- controlled

74

Rats (n=63) Baboons (n=11)

Rats: rivaroxaban 2 mg/kg.

Baboons: Rivaroxaban 0.6 mg/kg followed by 0.6 mg/kg/h

Rats: 4F-PCC (Beriplex) 25 and 50 U/kg;

aPCC (FEIBA) 50 and 100 U/kg; rFVIIa 100 and 400 mcg/kg.

Baboons: aPCC (FEIBA) 50 U/kg and rFVIIa 210 mcg/kg

Rats: 4F-PCC 50 U/kg significantly reduced BT (25 U/kg no significant reduction); aPCC (FEIBA) 50 and 100 U/kg significantly reduced BT; rFVIIa 400 mcg/kg significantly reduced BT (but 100 mcg/kg did not); reductions of TAT were significant with all three agents. Baboons: aPCC reduced BT but showed rebound c/w DIC (TAT went up along with the BT); rFVIIa had milder effect on BT but no rebound later.

Herzog et al, 2015

Animal model (kidney incision). Placebo-controlled

22

Rabbits)

Edoxaban

1,200 mcg/kg

4F-PCC (Beriplex) 50 U/kg

4F-PCC significantly reduced total blood loss and time to hemostasis. It also reduced (but did not correct) PT and WBCT.

Godier et al, 2012

Animal model (carotid injury followed by ear bleeding lesion and hepatosplenic bleeding lesion).

Placebo- controlled

48

Rabbits

Rivaroxaban

5 mg/kg

4F-PCC (Kaskadil) 40 U/mL and rFVIIa 150 mcg/kg

4F-PCC and rFVIIa partially improved the coagulation parameters, but did not reduce the bleeding time or blood loss. Neither therapy induced thrombosis.

Martin et al, 2013

Animal model (carotid injury followed by ear bleeding lesion and hepatosplenic bleeding lesion).

Placebo- controlled

63

Rabbits

Apixaban

0.4 mg/kg followed by 0.6 mg/kg/h

4F-PCC (Kanokad) 60 U/mL; rFVIIa 240 mcg/kg; Fibrinogen concentrate 300 mg/kg

None reduced blood loss. rFVIIa was the only one to reduce bleeding time. 4F-PCC and rFVIIa improved laboratory parameters partially. Fibrinogen actually increased blood loss. None induced thrombosis

Fukuda et al, 2012

Animal model (planta template bleeding and thrombosis model)

6 to 9 per group

Rats

Edoxaban (plasma concentration 150 and 300 ng/ml)

rFVIIa

0.3, 1, 3 mg/kg

aPCC (FEIBA)

50 and 100 U/kg

rFVIIa and aPCC reduced bleeding time and corrected PT and TAT values. None induced thrombosis.

Lu et al, 2014

Animal models of blood loss (including mice, rats, and rabbit model of liver laceration)

Mice

Rats

Rabbits

Rivaroxaban

(in mice: 50 mg/kg; in rats: 7.8 fold increase in plasma concentration; in rabbits: 1 mg/kg)

r-antidote (andexanet alpha)

Dose dependent reduction in blood loss (> 80%) and correction of anti-FXa activity.

Direct Thrombin Inhibitors

Author, year

Design

Subjects

Condition

Drug reversed


Outcome/Results/Limitations

Lauer A, 2011

Prospective animal study

244

ICH induced in mice

Dabigatran, warfarin, lepirudin, heparin, fondaparinux

none

No ICH expansion with dabigatran compared to warfarin

Dabigatran: significant aPTT prolongation, p

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