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 / Retrospective case series / 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 / Retrospective Case series / 7 / Other / warfarin / rFVIIa / INR corrected after rFVIIa, coagulation parameters improved
Brown, C. V.l, 2012 / Retrospective cohort / 23 / TBI / warfarin / rFVIIa, / Patients receiving rFVIIa at outlying hospital had lower INRs than those that did not, P=0.002
Wojcik, C, 2009 / Retrospective Cohort / 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 / Retrospective Cohort / 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 / Retrospective Case series / 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 / Retrospective Case series / 414 / ICH / warfarin / FFP / FFP incompletely reversed INR after warfarin use
Menzin, J, 2012 / Retrospective Case series / 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 / Retrospective Case series / 4 / EDH(1), SDH(3) / warfarin / FFP, rFVIIa / INR reversed effectively. 1 death, one good outcome, 2 excellent outcomes
Amin, A, 2012 / Retrospective Case series / 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 / Retrospective case series / 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 standardtherapy cohort.
Goldstein, J, 2006 / Retrospective Case series / 69 / ICH / warfarin / FFP/Vit K / Early time to treatment did not improve outcomes
Khorsand, N, 2011 / Retrospective Cohort / 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 / Retrospective Case series / 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 / Retrospective Case series / 88 / ICH / warfarin / PCC / early administration of PCC improved survival but not functional outcome
Huttner, H. B., 2006 / Retrospective Case series / 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 / Retrospective Cohort / 85 / ICH / warfarin / PCC / INR reduction similar, but possibly decreaseduse of other blood products needed in PCC group; cost lower in PCC group
Kalina, M, 2008 / Retrospective Cohort / 111 / TBI / warfarin / PCC / INR reversal was better and time to OR more favorable in PCC cohort
Kuwashiro, T, 2011 / Retrospective Case series / 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 / Retrospective cohort / 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 / Retrospective Case series / 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 / Retrospective Case series / 17 / Other / warfarin / PCC / PCC + VitK significantly decreased INR, plasma levels of coagulant factors increased immediately after administration; PCC alone decreased INR initially, but came back up 12-24hr later; VitK didn't significantly change INR until 12-24hr after
Sarode, R, 2012 / Retrospective Case series / 11 / ICH / warfarin / PCC + rFVIIa / INR was corrected consistently, time to dosing was faster than FFP
Makris, M., 1997 / Retrospective Case series / 41 / Other / warfarin / PCC + Vit K / PCC & FFP reversed INR elevations due to warfarin, PCC predicts INR response
Toth, P, 2012 / Retrospective Case series / 131 / ICH / warfarin / PCC + Vit K / Prolonged time to PCC in most patients, shorter in ICH; Vit K also prolonged
Mohrien, K, 2014 / Retrospective Case series / 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 / Retrospective Case series / 58 / Other / warfarin / PCC +/- FFP / INR reversal was not different with or without FFP; PCC generally effective, 4 thromboses seen
Wozniak, A, 2012 / Retrospective Cohort / 150 / Other / warfarin / PCC +/- VitK / Octaplex significantly decreased INR, maintained for up to 30hr; hemostasis in 57% of non-CNS patients, 50% hemostasis in CNS patients; VitK given to 107 patients. Of note, dosing is not well reported & unclear how that impacted the results
Yasaka, M, 2004 / Retrospective Case series / 42 / 2,5,7 / warfarin / PCC +/- VitK / PCC + VitK significantly decreased INR, other procoagulant factors increased immediately after administration; PCC alone decreased INR initially, but came back up 12-24hr later; VitK did not significantly change INR until 12-24hr after
Chapman, S, 2011 / Retrospective cohort / 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 / Retrospective Cohort / 85 / TBI / warfarin / PCC, rFVIIa / PCC is safe and effective in treating coagulopathy in TBI while reducing costs and resource use
Fredriksson, K, 1992 / Retrospective Case series / 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 / Retrospective Case series / 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 / Retrospective Cohort / 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 / Retrospective Case series / 11 / Other / warfarin / rFVIIa / INR correction better with rFVIIa than PCC
Robinson, M, 2010 / Retrospective Case series / 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 / Retrospective Cohort / 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 / Retrospective Case series / 27 / Other / warfarin / Vit K / Thrombosis off OAC is rare, good recovery is typical after holding or reversing warfarin
Berwaerts, J, 2000 / Retrospective Cohort / 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 / Intervention therapy / 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 / Healthy subjects (plasma donors) / 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 / Healthy subjects (plasma donors) / 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 / Healthy subjects (plasma donors) / 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 / Healthy subjects (plasma donors) / 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 / Healthy subjects(plasma donors) / 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 / Intervention therapy / 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<0.001, pronounced dTT increase, p=0.002; pretreatment with Dabigatran or lepirudin reduced factor II activity; dabigatran: ICH volume no difference, functional outcome not different
Komori M, 2014 / Retrospective case series / 9 / Intracranial hemorrhage / Dabigatran / Dabigatran was stopped, no reversal agent given / Discharge / 3 months 3 patients recovered, 1 pt. mRS 1, 1 pt. mRS 4
No increase in hemorrhage size
Pragst I, J, 2012 / Prospective controlled animal study / 28+ / Kidney injury induced bleeding in rabbits / Dabigatran / PCC (Beriplex P/N) 20, 35, 50 IU/kg in vivo, N=15 / in vitro plasma samples from rabbits 0.1, 0.2, 0.3, 0.4, 0.5 mg/kg dabigatran PCC 12.5, 25, 50, 75, 100 U/kg in vitro / 1. Blood loss 5.44 ml decline with each increment of PCC 10 IU/kg (P=0.002), at 35 IU/kg blood loss reduced to 18.8 ml vs 29 ml in the saline group ; 2. Time to hemostasis: 20 min with saline, decline with increasing PCC doses to median of 5.7 min at 50 IU/kg (P<0.001) ; 3. PCC increased peak thrombin generation by 31.9 nM per 10 IU/kg PCC, PCC shortened PT by 0.335 s per 10 IU/kg PCC, no change in PTT at 10 or 40 min after PCC.
Herzog E, 2014 / Prospective, placebo controlled animal study / 60 / AV Shunt induced between carotid artery and jugular vein + kidney incision in rabbits / Dabigatran / PCC 50 or 300 IU/kg / Shunt thrombosis after PCC administration was prevented by dabigatran at all doses. PCC attenuated blood loss from kidney injury at moderate dabigatran doses.
Eerenberg E, 2011 / Prospective randomized, placebo-controlled crossover study / 12 / Healthy individuals / Dabigatran and rivaroxaban / PCC (4F, Cofact) 50 U/kg / Dabigatran: PCC had no significant effects on aPTT, ETP lag time, TT, or ECT
Hoffman M, 2015 / Prospective animal and in vitro study / 12 / Saphenous bleeding induced in mice and plasma from healthy individuals / Dabigatran / rFVIIa 124, 270, 540 mcg/kg and 4 factor PCC (Beriplex, Kcentra) 25,50 IU/kg / PCC improved thrombin generation and normalized hemostasis time at therapeutic and supratherapeutic dabigatran levels