Thrombosis Research 133 S2 (2014) S158–S166

Contents lists available at ScienceDirect

Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h o m r e s

Potential antidotes for reversal of old and new oral anticoagulants Deepa Suryanarayana,b, Sam Schulman*a a

Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada Department of Medicine, University of Calgary, AB, Canada

b

ARTICLE

INFO

Keywords: Bleeding Antidote Direct thrombin inhibitors Factor Xa inhibitors Warfarin Heparin

ABSTRACT

The prescription of new oral anticoagulants is on the rise. As opposed to vitamin K antagonists and heparins the new agents have single targets in the coagulation cascade, more predictable pharmacokinetics and they lack validated and available antidotes. In general, the new agents have similar or lower bleeding risk than vitamin K antagonists, especially risk of intracranial bleeding. Risk factors for bleeding are typically the same for old and new anticoagulants. Old age, renal dysfunction and concomitant antiplatelet agents seem to be recurring risk factors. Adequate supportive care and temporary removal of all antithrombotic agents constitute the basis for management of serious bleeding complications. With the exception of vitamin K (for vitamin K antagonists) and protamine (for heparin) the same array of prohemostatic agents – unactivated or activated prothrombin complex concentrate, and activated factor VIIa – have been tried for almost all anticocoagulants in different models, and for some agents also in patients, with varying success. Hemodialysis can reduce the level of dabigatran efficiently and activated charcoal may be used for very recent oral ingestion of lipophilic agents. In view of the shorter half life of the new agents compared to warfarin the need for reversal agents may be less critical. Nevertheless, highly specific reversal agents for the thrombin- and factor Xa-inhibitors are under development and might be available within two years. © 2014 Elsevier Ltd. All rights reserved.

Introduction Vitamin K antagonists (VKA) have been widely used for the prevention and treatment of arterial and venous thromboembolism for more than 50 years. During the last ten years the clinical armamentarium has expanded to include several new oral anticoagulants (NOACs) based on high quality evidence from large randomized clinical trials [1]. These agents have several advantages over the VKA with more predictable pharmacokinetics and pharmacodynamics, fewer drug and food interactions allowing fixed dose regimens and eliminating the need for regular monitoring. However unlike for warfarin there are no specific antidotes available for urgent reversal and there is little to no evidence to guide practical management when patients present with bleeding complications or need reversal for urgent interventional procedures. A recent population based review noted rapid growth in the uptake of NOACs, in particular dabigatran, within the 2 years of its approval in Ontario, Canada, specifically in patients aged 85 years and older [2]. There was also a 14% decline observed in warfarin prescriptions. This highlights the need for evaluation of therapeutic strategies to reverse the anticoagulant state. Our review will focus on the

* Corresponding author at: Thrombosis Service, HHS-General Hospital, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada. Tel.: 1-905-5270271, ext 44479; fax: 1-905-5270271. E-mail address: [email protected] (S. Schulman). 0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.

available literature and suggest practical strategies for reversal and management of both the older and newer anticoagulants. Mechanisms of action of antithrombotic agents Vitamin K antagonists These agents inhibit the regeneration of vitamin K, a cofactor in the gamma carboxylation of coagulation factors II, VII, IX and X as well as protein C, S and Z. The pharmacodynamics and pharmacokinetics of the most widely used VKA, warfarin, are well described elsewhere [3]. The anticoagulant effects of warfarin are affected by genetic variability of involved cytochrome P450 and vitamin K epoxide reductase enzymes, multiple drugs and dietary supplements. Due to these interactions constant monitoring is required to maintain therapeutic international normalized ratio (INR). Whether genotyping would improve warfarin dose prediction and optimization was studied in three recently published randomized trials [4-6]. One trial showed that genotype based dosing was similar to clinically guided dosing of warfarin in the initial 4 weeks of anticoagulation and the second trial showed similar results for acenocoumarol or phenprocoumon during 12 weeks of initiation therapy. The third trial showed that pharmacogenetic based dosing was associated with a higher percentage of time in therapeutic range versus standard dosing during the first 12 weeks of warfarin initiation but none of the trials demonstrated a benefit in clinically important outcomes.

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

Heparins Unfractionated heparin (UFH) is a mixture of sulfated glycoaminoglycans of varying molecular weight and inhibits several coagulation factors by binding to antithrombin causing a conformational change and augmenting its inhibition 1000 fold. Low molecular weight heparin (LMWH) is obtained by depolymerization and/or fractionation of UFH and has predominant factor Xa inhibiting effect. Fondaparinux is a pentasaccharide that effectively binds and potentiates antithrombin to block factor Xa. The half life of UFH following intravenous injection is 1 to 2 hours and the half life of different LMWHs ranges from 3 to 12 hours. The limitations of heparin are based on its pharmacokinetic and biophysical properties [7]. Pharmacokinetic limitations result in variable anticoagulant response to heparin and are caused by antithrombin independent binding of heparin to plasma proteins and proteins released from platelets and endothelial cells. Biophysical limitations include osteopenia and heparin induced thrombocytopenia. These limitations are less evident with LMWH. Oral direct thrombin inhibitors Thrombin plays a key role in the coagulation cascade by mediating the conversion of fibrinogen to fibrin as well as physiologically activating platelets, several other coagulation factors, the protein C-pathway and endothelial receptors. Ximelagatran was the prototype oral drug that was first developed in this family but was subsequently withdrawn from the market due to serious hepatic side effects [8]. Dabigatran etexilate is a prodrug that does not have the risk profile of its predecessor, with a bioavailability of 6.5%. Its half life is 12-17 h in patients with normal renal function and it reaches the maximum serum concentration within 1.5-3 h after ingestion. It is 80% eliminated by the renal route and 35% protein bound [9]. Dabigatran demonstrated similar efficacy as enoxaparin for prophylaxis after hip [10,11] and knee arthroplasty [12] and was as effective as warfarin for acute management [13] and extended maintenance therapy for venous thromboembolism (VTE) [14]. It was non-inferior to warfarin (110 mg bid) and superior to warfarin (150mg bid) for stroke prevention in atrial fibrillation [15]. Based on these clinical trials dabigatran is currently approved for stroke prophylaxis in atrial fibrillation (SPAF) (Europe, North America) and for VTE prevention after major orthopedic surgery (not in the United States).

S159

bleeding complications. Two phase III trials found that apixaban was more effective for stroke prevention than either aspirin or warfarin in patients with atrial fibrillation, with a similar (versus aspirin) [27] or improved (versus warfarin) [28] safety profile. It was non-inferior to warfarin in treatment of VTE and was associated with significantly lower bleeding rates [29]. Based on these studies it also has been approved for SPAF (North America, Europe) and VTE prevention after major orthopedic surgery. Edoxaban has also recently been evaluated as an alternative to warfarin in phase III trials for VTE [30] and atrial fibrillation [31] demonstrating non-inferiority in both patient populations with significantly lower rates of bleeding. Bleeding rates and risk factors for bleeding on anticoagulants Vitamin K antagonists and heparins Regardless of the choice of anticoagulant the risk of bleeding remains a threat even when maintained within therapeutic ranges. The use of VKA increases the risk of major bleeding by 2-3% per year and the risk of intracranial hemorrhage by approximately 0.2% per year [32]. Some of the determinants of major bleeding have been identified and include the intensity of anticoagulation, concomitant use of drugs that interfere with hemostasis like antiplatelet, non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors, patient characteristics (age, comorbidities like hypertension, diabetes mellitus, cerebrovascular disease, ischemic stroke, cardiovascular disease, renal insufficiency, liver disease, malignancy and alcoholism) and the length of therapy [33]. The incremental risk of major hemorrhage with heparins varies between 0% and 2% [33]. The risk is dependent upon the intensity of anticoagulation, underlying disease and concomitant medications similar to VKAs. Renal failure, patient age, and sex have also been implicated as risk factors for heparin-induced bleeding in case series [33]. LMWH should be used with caution in patients with impaired renal function and evidence exists that the resultant bioaccumulation may cause bleeding [34]. Prophylaxis with fondaparinux at a daily dose of 2.5 mg is associated with less bleeding than a therapeutic dose of LMWH [35] but similar bleeding as UFH [36] and prophylactic LMWH [37]. Time of first injection was inversely related to risk of major bleeding as well as overt bleeding in one meta-analysis of studies with fondaparinux and age has also been determined as a risk factor [37].

Oral factor Xa inhibitors The new anticoagulants Rivaroxaban and apixaban are the first agents approved from this class of drugs. They act by reversibly blocking factor Xa at the active site. Their bioavailability is higher compared to that of dabigatran (rivaroxaban-80%, apixaban-60% and edoxaban-50%). Peak concentration is achieved within 1-4 h. They are less dependent on renal excretion (rivaroxaban-33% [active drug], apixaban- 25% and edoxaban-35%) [16]. Rivaroxaban was evaluated in a series of clinical trials in patients undergoing major orthopedic surgery for thromboprophylaxis and demonstrated higher efficacy compared to enoxaparin with similar bleeding rates [17-20]. It was noninferior to warfarin in patients with atrial fibrillation [21] and for acute and extended management of VTE [22,23]. This has led to its approval for thromboprophylaxis after major orthopedic surgery, SPAF and VTE treatment. Apixaban was also compared to enoxaparin in patients undergoing knee [24,25] and hip replacement surgery [26] and was shown to be equally effective with significantly fewer

The NOACs have shorter half-life and wider therapeutic window and are speculated to have lower rates of bleeding. Theoretically the same determinants or factors considered being predictive risk factors for increased bleeding risk for VKAs are applicable to the NOACs. Renal impairement is an important risk factor given that the agents are renally excreted. In a post hoc analysis of the major bleeding events in the RE-LY study only age was determined to be an independent risk factor [38]. In a recent prespecified analysis of the RE-LY study age was also found to be the most important covariate and bleeding outcomes were correlated with dabigatran plasma concentrations [39]. In a longterm follow-up study of cohorts from the randomized trial in atrial fibrillation dabigatran was associated with higher bleeding rates at the 150 mg twice daily dose in comparison with 110 mg twice daily [40]. Rates of major hemorrhage were 3.74% and 2.99% per year on dabigatran 150 mg and 110 mg, respectively (hazard ratio, 1.26; 95% confidence interval, 1.04-1.53). In another subgroup

S160

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

Table 1 Risk of major bleeding associated with NOACs in comparison with standard anticoagulant therapy/placebo: data from phase III randomized controlled trials

Agent

Clinical Indication

Trial

Total no. of patients

Dabigatran

VTE prophylaxis after hip/knee arthroplasty

RE-NOVATE

Atrial fibrillation

VTE treatment

Rivaroxaban

Apixaban

Dose

Comparator

3494

150 mg o.d. 220 mg o.d.

Enoxaparin 40 mg o.d.

33 days

1.3% vs 1.6% 2% vs 1.6%

RE-NOVATE II

2,055

220 mg o.d.

Enoxaparin 40 mg o.d.

32 days

1.4% vs 0.9%

RE-MOBILIZE

2,615

150 mg o.d. 220 mg o.d.

Enoxaparin 30 mg o.d.

14 days

0.6% vs 1.4% 0.6% vs 1.4%

RE-MODEL

2,076

150 mg o.d. 220 mg o.d.

Enoxaparin 40 mg o.d.

8 days

1.5% vs 1.3% 1.3% vs 1.3%

RE-LY

18,113

110 mg bid 150 mg bid

Warfarin

24 months

2.8% vs 3.5% 3.3% vs 3.5%

RE-COVER

2,564

150 mg bid

Warfarin

6 months

1.6% vs 1.9%

RE-COVER 2

2,568

150 mg bid

Warfarin

6 months

1.2% vs 1.7%

RE-MEDY

2,866

150 mg bid

Warfarin

18 months

0.9% vs 1.8%

RE-SONATE

1,353

150 mg bid

Placebo

18 months

0.3% vs 0%

RECORD-1

4541

10 mg o.d.

Enoxaparin 40 mg o.d.

35 days

0.3% vs 0.1%

RECORD-2

2509

10 mg o.d.

Enoxaparin 40 mg o.d.

35 days

0.08% vs 0.08%

RECORD-3

2531

10 mg o.d

Enoxaparin 40 mg o.d

12 days

0.6% vs 0.5%

RECORD-4

3148

10 mg o.d

Enoxaparin 30 mg bid

12 days

0.7% vs 0.3%

Atrial fibrillation

ROCKET-AF

14,264

20 mg o.d.

Warfarin

20 months

5.6% vs 5.4%

VTE treatment

EINSTEIN-DVT

3449

15 mg bid and then 20 mg o.d.

VKA

3-12 months

0.8% vs 1.2%

EINSTEIN-PE

4832

15 mg bid and then 20 mg o.d.

VKA

3-12 months

1.1% vs 2.2%

EINSTEIN-EXT

1197

20 mg o.d.

Placebo

6-12 months

0.7% vs 0%

ADVANCE-1

3195

2.5 mg bid

Enoxaparin 30 mg bid

12 days

0.7% vs 1.4%

ADVANCE-2

3057

2.5 mg bid

Enoxaparin 40 mg o.d.

12 days

0.6% vs 0.9%

ADVANCE-3

5407

2.5 mg bid

Enoxaparin 40 mg o.d.

35 days

0.8% vs 0.7%

VTE prophylaxis after hip/knee arthroplasty

VTE prophylaxis after hip/knee arthroplasty

Atrial fibrillation

VTE treatment

Edoxaban

Mean duration

Major bleeding (%), NOAC vs comparator

ARISTOTLE

18,201

5 mg bid

Warfarin

1.8 years

2.2% vs 3.1%

AVERROES

5599

5 mg bid

Aspirin

1.1 years

1.4% vs 1.2%

AMPLIFY

5395

5mg bid

Warfarin

6 months

0.6% vs 1.8%

AMPLIFY-EXT

2486

2.5 mg bid 5 mg bid

Placebo

12 months

0.2% vs 0.5% 0.1% vs 0.5%

VTE treatment

HOKUSAI-VTE

4921(DVT) 3319(PE)

60 mg o.d. 30 mg o.d.

Warfarin

3-12 months

1.4% vs 1.6% 1.5% vs 3.1%

Atrial fibrillation

ENGAGE AF-TIMI 48

21,105

60 mg o.d. 30 mg o.d.

Warfarin

907 days

2.8% vs 3.4% 1.6% vs 3.4%

NOAC – new oral anticoagulant; VTE – venous thromboembolism; VKA – vitamin K antagonist; DVT – deep vein thrombosis; PE – pulmonary embolism

analysis concomitant antiplatelet drug therapy increased the risk of major bleeding both in patients treated with dabigatran and with warfarin [41]. A higher CHADS2 risk score (3 points) was also associated with increased risk of dabigatran-associated major bleeding and intracranial hemorrhage [42]. Analysis of data from the rivaroxaban trial in atrial fibrillation showed that older age, male sex, history of diabetes, body mass index and decreased creatinine clearance were independent predictors of major bleeding [43]. Subgroup analysis of the apixaban trial in atrial fibrillation showed increased rates of major bleeding with higher risks for stroke (CHADS2 or CHA2DS2-VASc scores) and for bleeding (HAS-BLED score) [44]. In contrast, lower rates

of intracranial hemorrhage occurred in patients with higher CHADS2 scores compared to those with lower scores. The relative risk reduction in intracranial bleeding tended to be greater in patients with HAS-BLED scores of 3 than in those with HASBLED scores of 0-1. Major bleeding rates in phase III clinical trials with NOACs have been summarized in Table 1. In the absence of head to head clinical trials with the NOACs few indirect comparisons using network meta-analysis have been published addressing safety and efficacy of these agents. There are a number of constraints and limitations related to the method used in such indirect comparison analysis and hence one has to employ caution

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

S161

Table 2 Reversal strategy recommendations for old and new anticoagulants Agent

Pharmacological characteristics

Target

Lab investigations Reversal strategies*

Vitamin K antagonists

T½ 36-48 hours (Warfarin), liver metabolism

Vitamin K dependent factor synthesis

PT (INR)

Vitamin K, PCC, activated PCC, FFP

Unfractionated heparin

T½ (1-2 hours)

Antithrombin, factor Xa, factor IIa

aPTT

Protamine sulfate

Low molecular weight heparin

T½ (3-13 hours), renal excretion

Predominant factor Xa

Anti Xa

Protamine sulfate partially helpful; rFVIIa

Dabigatran

T½ (14-17 hours), 80% renal excretion

Factor IIa

APTT (screen) Hemoclot

activated PCC, recombinant FVIIa, PCC

Rivaroxaban

T½ (9-15 hours), 33% renal excretion

Factor Xa

PT (screen) Anti Xa

PCC, activated PCC, recombinant FVIIa

Apixaban

T½ (9-14 hours), 25% renal excretion

Factor Xa

Anti Xa

PCC, activated PCC, recombinant FVIIa

Edoxaban

T½ (6-11 hours), 50% renal excretion

Factor Xa

Anti Xa

PCC, activated PCC, recombinant FVIIa

INR-International normalized ratio; FFP- Fresh frozen plasma; PCC-Prothrombin complex concentrate; PT-prothrombin time; aPTT-activated prothrombin time; VKA-Vitamin K antagonists *Reversal agents with modestly proven efficacy and lack of specific antidote

during interpretation of the results of these studies. Two indirect comparisons of the safety and efficacy of three NOACs have been published recently. One of the analyses, which included nine studies comparing VKAs with NOACs for acute VTE, concluded that the NOACs had similar risk of recurrence of VTE compared to VKA and rivaroxaban was associated with reduced risk of bleeding compared to warfarin but not to other NOACs [45]. Another indirect comparison analysis concluded that apixaban caused significantly less major bleeding (by 26%, p=0.0003) and gastrointestinal bleeding than dabigatran 150 mg twice daily and less intracranial bleeding than dabigatran 110 mg twice daily [46]. According to the same analysis apixaban had lower risk of major bleeding when compared to rivaroxaban (by 34%, p4 oral vitamin K at doses between 1 and 2.5 mg will lower INR within 24 hours [51]. Despite the advantage of rapid lowering of INR with intravenous vitamin K compared to oral, similar degrees of INR correction have been noted at 24 hours [52]. One recent randomized study found no difference in bleeding or other complications in non-bleeding patients with INR values of 4.5–10 who were treated with vitamin K or placebo [53]. This study has been criticized in terms of its study design, patient selection, dosage of vitamin K and unexpected high rate of bleeding in the control group [54]. It is, however, still reasonable to consider giving oral vitamin K in patients with INR of 5-8 if they are deemed to be at high risk of bleeding. In case of life threatening bleeding 2.5 mg of vitamin K will achieve complete reversal in most patients but doses up to 10 mg would be justified for very high INR levels or concomitant liver impairment. Plasma and prothrombin complex concentrate Rapid correction of warfarin in the event of life threatening bleeding can also be achieved by administration of functionally normal coagulation factors. Fresh frozen plasma (FFP) is readily available in most centers, contains vitamin K-dependent factors and is useful in reversal of warfarin. However it has to be administered in large volumes (>1500 ml) to achieve meaningful increase in coagulation factors in the event of ongoing bleeding and continued loss of coagulation factors. This may pose a problem especially in the elderly where rapid infusion cannot be achieved. It also carries the disadvantage of requiring thawing time along with a small risk of transfusion-associated infection. In contrast to FFP, prothrombin complex concentrate (PCC) contains factors II, IX, X and VII at an approximately 25 times higher concentration than that in plasma, thus reducing the volume required for reversal significantly. This advantage translates into a rapid onset of action and PCC carries reduced risk of transfusion associated circulatory overload or transfusion associated lung injury. Rapid correction was achieved effectively with PCCs in one cohort study compared to FFP [55]. This study also found that complete reversal was not feasible with FFP when INR was greater than 5 due to large volumes required. There are two types of PCC products and they vary in their clotting factor

S162

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

Table 3 Recommendations for supratherapeutic INR without major bleeding [1] INR

Management

Vitamin K dose

>therapeutic range, but 10

Hold warfarin and administer vitamin K, increase frequency of monitoring, repeat vitamin K as needed and resume at appropriate dosage once INR is therapeutic

2.5 to 5 mg orally as one dose

INR-International normalized ratio

content with regards to amount of factor VII. Three-factor PCC contains smaller amounts of factor VII. In one study three-factor PCC did not satisfactorily lower INR due to lower factor VII content. Three-factor PCC for warfarin reversal with additional FFP provided greater INR reduction [56]. In a recent randomized study enrolling 212 evaluable patients comparing four-factor PCC and FFP in patients with acute major bleeding on warfarin, four-factor PCC normalized INR within 30 minutes and the fluid overload was lower in the PCC group (5%) compared to the FFP group (13.2%) [57]. This trial has led to approval in the United States of four-factor PCC (Kcentra™, CSL Behring, Marburg, Germany) for urgent warfarin reversal. Thromboembolic complications are reported infrequently in the literature with PCCs but the potential for VTE should be considered when using these agents for reversal of warfarin [58]. Recombinant factor VIIa Recombinant factor VIIa (rFVIIa) has been evaluated in a small number of studies for warfarin reversal. One retrospective study found that use of rFVIIa was associated with decreased time to reverse INR without any mortality benefit [59]. The same study also found a non-significant increased frequency of thromboembolism with rFVIIa compared to standard treatment for warfarin reversal. Another small retrospective analysis found that correction of INR was more reliably obtained with rFVIIa than PCC for warfarin related intracranial hemorrhage [60]. The risk of thromboembolism is present with rFVIIa [61,62]. One meta analysis found that off label treatment with high doses of rFVIIa significantly increased the risk of arterial but not venous thromboembolic events, especially in the elderly [63]. Given the limited data and the potential risk, the role of rFVIIa in warfarin reversal remains unclear at this time. Activated PCC The role of activated PCC (FEIBA®, Baxter, Deerfield, IL) for warfarin reversal has been explored in a few studies, most of which are retrospective [64,65]. One retrospective study found that administration of activated PCC resulted in lower subsequent INR when compared with FFP and shorter time elapsed from drug administration to an INR 1.4 when compared with FFP with no significant differences in survival or in the length of hospital stay [65]. Five adverse events (3 possible cardiac ischemia, 1 deep vein thrombosis and 1 death due to sepsis) were however observed in the activated PCC arm raising concerns for thromboembolic complications. Reversal of heparins Protamine Protamine sulfate has been widely used to reverse the effect of UFH for nearly 30 years. While protamine can completely reverse the effect of UFH at dose of 1 mg/100 units heparin, it neutralizes

LMWH or other heparinoids like danaparoid only partially since it only reverses the inhibition of factor IIa (thrombin). There is approximately 1% risk of anaphylaxis with protamine secondary to histamine release mainly noted during cardiac surgeries [66]. Thrombocytopenia with protamine administration has also been reported [67]. One recent study demonstrated that platelet-activating anti–protamine-heparin antibodies, present at the time of protamine infusion were associated with more significant thrombocytopenia and increased risk of thromboembolic complications in patients undergoing cardiac surgery [68]. Recombinant FVIIa A good number of studies demonstrate that rFVIIa is effective in reducing bleeding in LMWH-induced bleeding in animal models [69,70] , patients with warfarin associated intracranial bleed [71] and healthy volunteers on fondaparinux [72] or idraparinux [73] . The dose at which beneficial clinical effect was achieved in these trials was 90 g/kg. Another study demonstrated that rFVIIa can rapidly and safely reverse the hemorrhagic adverse effects associated with excessive levels of LMWH in patients with preexisting hypercoagulable conditions and/or acute VTE [74]. Pentasaccharide reversal Pentasaccharides have no specific antidotes and are not reversed by protamine. Hemodialysis may reduce plasma levels of fondaparinux by only approximately 20%. Recombinant FVIIa has demonstrated some efficacy in healthy volunteers and in vitro studies [75,76]. In a recent study blood samples from healthy volunteers were spiked with heparin, enoxaparin, fondaparinux, argatroban or bivalirudin and the effect of rFVIIa was analyzed with thromboelastography (TEG). Blood samples were also obtained from 9 patients who were stably anticoagulated on heparin (n=2), bivalirudin (n=3), argatroban (n=1) and fondaparinux (n=1) with or without ex vivo addition of rFVIIa or placebo. In the TEG analysis rFVIIa exerted similar reversal effects on anticoagulated patients as on ex vivo samples, thus supporting use of rFVIIa in the reversal of these agents [77]. Thromboembolic complications remain a concern with rFVIIa in up to 7% of patients. New oral anticoagulants and management of bleeding complications Management options on NOACs should be individualized based on severity of bleeding as well as indication of anticoagulation, patient attributable factors like age, comorbidities, duration since intake of last dose, dosage, concomitant antihemostatic therapies and site of bleeding. Supportive therapy In patients presenting with bleeding on NOACs general supportive measures such as fluid rescussitation and adequate

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

oxygenation should be instituted without any delay just as with any bleeding with older anticoagulants. A coagulation panel should be obtained immediately along with blood count and creatinine. Activated partial thromboplastin time (aPTT) has a linear response to dabigatran concentration up to the therapeutic range and should be useful to assess the presence of any significant concentration of dabigatran. A normal aPTT would essentially exclude dabigatran as a causative agent of the bleed. Similarly a normal prothrombin time (PT) would help exclude rivaroxaban as a causative factor. Hemoclot® (Hyphen BioMed, Neuville-sur-Oise, France) or dilute thrombin time would be the best test to evaluate therapeutic versus excess levels of dabigatran. Some algorithms for management of moderate to severe bleeding with NOACs have been published recently [78-81]. Simple discontinuation of NOACs would be enough to control mild bleeding in patients with normal renal function given the short half-life. Antiplatelet and anticoagulant agents should be discontinued and supportive measures like transfusions and specific or non-specific hemostatic agents should be administered. Local hemostatic measures including mechanical compression, endoscopic therapies for gastrointestinal bleeding, and angiographic coiling are usually safe and effective. Antifibrinolytic agents, despite lack of published evidence in the bleeding with NOACs, would be reasonable to initiate to help control the bleed. Direct thrombin inhibitors Oral activated charcoal Oral activated charcoal may absorb dabigatran effectively following a recent ingestion or overdose as demonstrated in an in vitro model [82]. Activated charcoal absorbed 99.9% of dabigatran suspended in acidic water in this model and its administration should be done within 1-2 h after ingestion of the drug given its quick onset of action. This treatment has not been tested in a clinical trial but has been reported in at least one case [83]. Hemodialysis or hemoperfusion Due to the low protein binding of dabigatran (35%) it could potentially be dialyzable in the event of life threatening bleed, intoxication or emergency reversal before surgery. Approximately 1/3 of a single dose of 50 mg dabigatran was removed by hemodialysis over a 2-hour period in six patients with end stage kidney disease [84]. A single center phase I study showed that up to 59.3% of dabigatran was eliminated in a 4-hour session [85]. Several recent case reports have reported successful reversal of dabigatran with hemodialysis [86-88]. However the technical issues of establishing central venous access with largebore catheters in fully anticoagulated patients along with the additional risk of bleeding will often be a limiting factor for this strategy. PCC and activated PCC Several animal studies have investigated effect of PCC on dabigatran induced bleeding in mice, rats and rabbits. In a mouse model of intracranial hemorrhage on high dose dabigatran, hematoma volumes were noted to be reduced with treatement with FFP or PCC compared to saline [89]. In the same experiment the volume was not smaller in mice treated with rFVIIa compared with saline. Another study demonstrated that rat (tail vein) bleeding time was significantly reduced by four-factor PCC [90]. In a phase 1 study of 12 healthy male volunteers receiving dabigatran versus placebo administration of four-factor PCC was unable to correct thrombin time, aPTT or ecarin clotting time [91]. Another case series also reported failure of PCC to manage

S163

dabigatran associated massive bleeding [92]. Hence currently there is no supportive evidence for the use of PCC in dabigatran reversal. An ex vivo study in healthy individuals on dabigatran showed good effect of reversal of impaired thrombin generation with activated PCC [93]. Similar results were noted in another ex vivo study in samples of patients on dabigatran [94]. Successful management of ablation-induced and dabigatran-associated pericardial tamponade with activated PCC was reported in one case [95]. Four additional cases have been published documenting successful use of activated PCC in dabigatran associated gastrointestinal bleed and intracranial bleed [96]. Activated PCC appears promising but data from well-designed clinical studies are needed. Increased risk of thromboembolic complications should also be given careful consideration with activated PCC. Recombinant activated factor VIIa In a rat tail bleeding model with dabigatran, rFVIIa was shown to reduce bleeding with partial normalization of aPTT [90]. However, in another animal model rFVIIa failed to reduce dabigatran-induced intracerebral hematoma expansion in mice [89]. In ex vivo treated plasma samples from healthy volunteers rFVIIa was unable to reverse anticoagulant effect of dabigatran [93]. In a series of 4 cases rFVIIa failed to control dabigatran associated bleeding in 3 patients [92]. In another case of dabigatran associated massive bleed following coronary artery by-pass surgery five doses of rFVIIa along with hemodialysis was reported to decrease bleeding [97]. Due to concomitant use of dialysis along with rFVIIa this data has to be carefully interepreted and hence makes it difficult to assess the real efficacy of the agent. Specific reversal agents A highly selective, humanized and specific monoclonal antibody fragment against dabigatran is currently in early clinical studies. It has demonstrated rapid inhibition of dabigatran anticoagulant acitivity in human plasma in vitro and in rats in vivo [98]. Factor Xa inhibitors Activated oral charcoal There are no studies reported on the use of oral charcoal for reversal of rivaroxaban either in animals or humans to the best of our knowledge. One study investigated enterohepatic recirculation of apixaban by adminstration of activated charcoal to bile duct cannulated rats and dogs. This study found that enterohepatic circulation of apixaban could be interrupted by activated charcoal even 3 h after ingestion in dogs [99]. Hemodialysis Given the high protein binding of rivaroxaban and apixaban hemodialysis is unlikely to remove these drugs from circulation. PCC Three animal studies are reported that have investigated effect of PCC on rivaroxaban. PCC prevented expansion of intracerebral hematoma in a murine model with rivaroxaban treatment and intracranial hemorrhage [100]. In a bleeding rabbit model on rivaroxaban, PCC partially improved aPTT and thromboelastographic clotting time but did not reverse the bleeding [101]. Similar results were obtained with rabbits treated with apixaban with no effect on blood loss but normalization of lab parameters [102]. An in vitro study using human plasma spiked with edoxaban showed that administration of PCC was

S164

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

able to significantly shorten the prolonged PT [103]. In a study in healthy individuals treated with rivaroxaban, PCC at a dose of 50 IU/kg normalized the prolonged PT [91]. So far there have been no published case studies evaluating PCC in rivaroxabanassociated bleeding.

fibrillation; CI – Confidence interval; FFP-Fresh frozen plasma; PCC-Prothrombin complex concentrate; rFVIIa-Recombinant factor VIIa; TEG-Thromboelastography; aPTT-Activated partial thromboplastin time; PT-Prothrombin time. Conflict of interest statement

Activated PCC and rFVIIa Activated PCC shortened PT in rats on edoxaban [103]. In another animal study in baboons infusion of activated PCC shortened the prolonged PT caused by high doses of rivaroxaban [104]. rFVIIa ex vivo in an edoxaban-treated rat model normalized PT [103]. Bleeding time in these rats also normalized following high doses of rVIIa at 3 mg/kg. In baboons treated with high doses of rivaroxaban minimal reduction of bleeding time and no effect on aPTT was noted with rFVIIa [104]. This agent had no effect on amount of blood loss but reduced bleeding time in rabbits treated with rivaroxaban or apixaban using Folts injury model [101]. Universal NOACs reversal agent A novel recombinant protein andexanet alfa (PRT064445 or PRT4445) is a factor Xa decoy with structural modifications rendering it hemostatically inactive. In preclinical studies it reversed the effect of fondaparinux and enoxaparin [105]. Early results of phase 2, double-blind, placebo-controlled study examining the reversal by andexanet alfa of the anticoagulant activity of rivaroxaban studied in 6 different dose cohorts in healthy subjects has recently been presented [106]. It demonstrated that PRT06445 is able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban in healthy subjects. Further phase 3 studies are currently underway. PER977 is another small synthetic molecule developed by Persosphere Inc and is under investigation as a potential antidote for several NOACs including dabigatran, rivaroxaban, apixaban and edoxaban [107]. In a standard rat tail bleeding model PER977 decreased bleeding and in ex vivo human plasma treated with dabigatran, rivaroxaban and apixaban PER977 showed reversal of anticoagulant effect. No adverse effects have been observed in animal models. Clinial trials are expected to start soon to further investigate the reversal effect. Conclusion Certainly with the growing influx of new agents the complexicity of antithrombotic therapy is increasing. Bleeding is a well known side effect of all antithrombotic agents. Specific reversal strategies and guidelines have made management of bleeding on the older agents seem relatively straight forward and safe but at the same time there is some evidence that initiating supportive measures would suffice for most of the bleeding complications on the newer agents due to their short half life [108]. There are also lower bleeding rates with the newer agents especially in terms of intracranial bleeding, which makes them appealing to certain high risk populations. Ongoing clinical trials hold promise with regards to specific reversal agents such as PCC, activated PCC, specific monoclonal antibody fragment (against dabigatran) and decoy factor Xa (for Xa inhibitors) for the newer anticoagulants and may change the face of bleeding management in the near future. Abbreviations VKA- Vitamin K antagonist NOAC- New oral anticoagulant; INR- International normalized ratio; UFH- Unfractionated heparin; LMWH-Low molecular weight heparin; VTEVenous thromboembolism; SPAF- Stroke prophylaxis in atrial

S. Schulman has received honoraria for work in study committees from Boehringer Ingelheim and research support from Boehringer-Ingelheim and Baxter. References [1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e152S-84S. Xu Y, Holbrook AM, Simpson CS, Dowlatshahi D, Johnson AP. Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis. CMAJ Open 2013;1:E115-E119. Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou G, et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PLoS One 2011;6:e27808. Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283-93. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294-303. Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013;369:2304-12. Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation 2001;103:2994-3018. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-8. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007;64:292-303. Eriksson B, Dahl O, Huo M, Kurth A, Hantel S, Hermansson K, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). Thromb Haemost 2011;105:721-9. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non-inferiority trial. Lancet 2007;370:949-56. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178-85. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med 2013;368:709-18. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res 127:497-504. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31-9. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-86. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al.

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

[21]

[22]

[23]

[24]

[25]

[26]

[27] [28]

[29]

[30]

[31]

[32]

[33]

[34] [35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:1673-80. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510. Buller HR, Prins MH, Lensing AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-15. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594-604. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-98. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:140615. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104. Douketis JD, Arneklev K, Goldhaber SZ, Spandorfer J, Halperin F, Horrow J. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, casefatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med 2006;166:853-9. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:257S-298S. Crowther M, Lim W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr Opin Pulm Med 2007;13:409-13. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-76. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute STsegment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006;295:1519-30. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833-40. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial. Circulation 2011;123:2363-72. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients in the RE-LY trial. J Am Coll Cardiol 2014;63:321-8. Connolly SJ, Wallentin L, Ezekowitz MD, Eikelboom J, Oldgren J, Reilly PA, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128:237-43. Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2013;127:634-40. Oldgren J, Alings M, Darius H, Diener HC, Eikelboom J, Ezekowitz MD, et al. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Ann Intern Med 2011;155:660-7. Halperin JL, Wojdyla D, Piccini JP, Lokhnygina Y, Patel MR, Breithardt G, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the ROCKET-AF Trial. International Stroke Conference, New Orleans, LA, 2012. Abstract 148.

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54] [55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63] [64]

[65]

S165

Lopes RD, Al-Khatib SM, Wallentin L, Yang H, Ansell J, Bahit MC, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: A secondary analysis of a randomised controlled trial. Lancet 2012;380:1749-58. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: Direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 2012;345:e7498. Lip GY, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012;60:738-46. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: A systematic review and meta-analysis of the literature. Circulation 2012;126:2381-91. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013;70:1486-90 . Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Jr., Faxon DP, Freed MD, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523-661. Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarinassociated coagulopathy. A randomized, controlled trial. Ann Intern Med 2002;137:251-4. Dezee KJ, Shimeall WT, Douglas KM, Shumway NM, O’Malley P G. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med 2006;166:391-7. Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 2001;115:145-9. Crowther MA, Ageno W, Garcia D, Wang L, Witt DM, Clark NP, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: A randomized trial. Ann Intern Med 2009;150:293-300. Swaim MW, Macik BG. Vitamin K to correct overanticoagulation. Ann Intern Med 2009;151:432-3; author reply 435. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997;77:477-80. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009;49:1171-7. Sarode R, Milling TJ, Jr., Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234-43. Dentali F, Marchesi C, Pierfranceschi MG, Crowther M, Garcia D, Hylek E, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011;106:429-38. Nishijima DK, Dager WE, Schrot RJ, Holmes JF. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med 2010;17:244-51. Pinner NA, Hurdle AC, Oliphant C, Reaves A, Lobo B, Sills A. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg 2010;74:631-5. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-85. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-8. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791-800. Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding. Am J Emerg Med 2013;31:1251-4. Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal

S166

[66]

[67] [68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81] [82]

[83] [84]

[85]

[86]

[87]

D. Suryanarayan and S. Schulman / Thrombosis Research 133 S2 (2014) S158–S166

of warfarin-induced coagulopathy. Int J Emerg Med 2009;2:217-25. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol 2008;103:192-6. Horrow JC. Protamine: a review of its toxicity. Anesth Analg 1985;64:34861. Bakchoul T, Zollner H, Amiral J, Panzer S, Selleng S, Kohlmann T, et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood 2013;121:2821-7. Chan S, Kong M, Minning DM, Hedner U, Marder VJ. Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin. J Thromb Haemost 2003;1:760-5. Lauritzen B, Hedner U, Johansen PB, Tranholm M, Ezban M. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost 2008;6:804-11. Lewis B, O’Leary M, Vinh T. Successful use of rVIIa (NovoSeven) to reverse enoxaparin (Lovenox) overdose in an adult patient with intracranial bleeding. Thromb Haemost 2001;Suppl:Abstr P2633. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002;106:2550-4. Bijsterveld NR, Vink R, van Aken BE, Fennema H, Peters RJ, Meijers JC, et al. Recombinant factor VIIa reverses the anticoagulant effect of the longacting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004;124:653-8. Firozvi K, Deveras RA, Kessler CM. Reversal of low-molecular-weight heparin-induced bleeding in patients with pre-existing hypercoagulable states with human recombinant activated factor VII concentrate. Am J Hematol 2006;81:582-9. Gerotziafas GT, Depasse F, Chakroun T, Samama MM, Elalamy I. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb Haemost 2004;91:531-7. Lisman T, Bijsterveld NR, Adelmeijer J, Meijers JC, Levi M, Nieuwenhuis HK, et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb Haemost 2003;1:2368-73. Young G, Yonekawa KE, Nakagawa PA, Blain RC, Lovejoy AE, Nugent DJ. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis 2007;18:547-53. Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012;126:2428-32. Akwaa F, Spyropoulos AC. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med 2013;15:288-98. Donadini MP, Ageno W, Douketis JD. Management of bleeding in patients receiving conventional or new anticoagulants: a practical and case-based approach. Drugs 2012;72:1965-75. Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 2013;35:391-8. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27. Woo JS, Kapadia N, Phanco SE, Lynch CA. Positive outcome after intentional overdose of dabigatran. J Med Toxicol 2013;9:192-5. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259-68. Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013;109:596-605. Chen BC, Sheth NR, Dadzie KA, Smith SW, Nelson LS, Hoffman RS, et al. Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Am J Kidney Dis 2013;62:591-4. Lal Y, Van Heukelom J. Dabigatran: a cause of hematologic emergency. Am J Med Sci 2013;346:190-3.

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012;46:e21. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011;42:3594-9. van Ryn J, Kink-Eiband M, Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood 2011;118:Abstract 2316. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9. Lillo-Le Louet A, Wolf M, Soufir L, Galbois A, Dumenil AS, Offenstadt G, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 2012;108:583-5. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217-24. Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013;35:222-4. Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in a lifethreatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013;41:e42-e46. Schulman S, Ritchie B, Goy JK, Nahirniak S, Almutawa M, Ghanny S. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol 2014;164:608-10. Warkentin TE, Margetts P, Connolly S, Lamy A, Ricci C. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012;119:2172-4. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554-62. Zhang D, Frost CE, He K, Rodrigues AD, Wang X, Wang L, et al. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: Administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos 2013;41:906-15. Zhou W, Zorn M, Nawroth P, Butehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013;44:771-8. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012;116:94-102. Martin AC, Le Bonniec B, Lecompte T, Fischer AM, Emmerich J, Samama CM, et al. Evaluation of recombinant activated factor vii, prothrombin complex concentrate and fibrinogen concentrate to reverse apixaban in a rabbit model. J Am Coll Cardiol 2012;59:E573 (Abstr 904-8). Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor xa inhibitor, with haemostatic agents. Thromb Haemost 2012;107:253-9. Gruber A, Marzec UM, Buetehorn U, Hanson S, Perzborn E. Reversal of the antihaemostatic effects of rivaroxaban by activated factor vii and activated prothrombin complex in primates. Haematologica 2009;94 (Suppl 2):181 (Abstr 449). Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446-51. Crowther M, Mathur V, Kitt M, Lu G, Conley PB, Hollenbach S, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors. Blood 2013 122:3636 (abstract). Laulicht B, Bakhru S, Lee C, Baker C, Jiang X, Mathiowitz E, et al. Small molecule antidote for anticoagulants. Circulation 2012;126:A11395 (abstract). Majeed A, Hwang H-G, Connolly S, Eikelboom J, Ezekowitz M, Wallentin L, et al. Management and outcomes of major bleeding on dabigatran or warfarin. Circulation 2013;128:2325-32.