SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Anticoagulant drugs are taken by millions of patients throughout the world. Warfarin has been the most widely prescribed anticoagulant for decades. In recent years, new oral anticoagulants have been approved for use, are being positioned as alternatives to warfarin, and represent an enormous market opportunity for pharmaceutical companies. Requests for urgent reversal of anticoagulants are not uncommon especially in the setting of critical bleeding. This review summarizes information on reversal of warfarin by vitamin K, plasma, prothrombin complex concentrates, and recombinant VIIa. In addition, we emphasize the lack of current evidence supporting reversibility of the new oral direct thrombin inhibitors and Factor Xa inhibitors. This review is presented to assist transfusion medicine specialists, hematologists, and other clinicians who prescribe blood components for reversal of drug-induced anticoagulation.


ABBREVIATIONS:
aPTT = activated

partial thromboplastin time

INR = international

normalized ratio

PCC(s) = prothrombin

complex concentrate(s)

PT = prothrombin

time

SNP(s) = single-nucleotide

polymorphism(s)

ANTICOAGULANT USE ON THE RISE

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Societies in the economically advantaged nations of the world are aging. The percentage of the US population over age 65 is expected to nearly double by 2050 resulting in an absolute increase from 40 million to 86 million individuals (see Fig. 1). Cardiovascular disease and stroke are common ailments of an elderly population. The CHADS2 score—a simple point scoring scale for congestive heart failure, hypertension, age greater than 75, diabetes mellitus, prior stroke, or TIA—is a clinical prediction tool used to estimate the risk of stroke in patients with atrial fibrillation. For the growing number of elderly individuals with atrial fibrillation, deliberate anticoagulation is a mainstay of stroke prevention.

image

Figure 1. Actual and projected elderly population in the United States. Data from US Census Bureau.

Download figure to PowerPoint

It is therefore no surprise that warfarin is among the most widely prescribed medications in the industrialized world representing a market of over $7 billion for the pharmaceutical industry. For 50 years this market has been dominated by derivatives of warfarin but in the past 2 years new oral anticoagulant drugs have been licensed and are being positioned by the pharmaceutical industry to replace warfarin. All anticoagulant therapies are accompanied by bleeding complications in some patients. This review summarizes highlights on the use of blood products for urgent reversal of drug-induced anticoagulation. The interested reader is referred to other more detailed reviews.1,2

WARFARIN ANTICOAGULATION

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Discovery of coumarin

In 1920, cows all over Wisconsin began to mysteriously die. On one farm, 21 of 22 cows bled to death after dehorning. At another location, 12 of 25 bulls bled to death after castration. Frank Schofield, a Canadian veterinary pathologist, investigated the mysterious disorder and discovered that the affected cows were eating moldy sweet clover mixed with their hay. By eliminating the moldy sweet clover the bleeding tendency went away, but the underlying cause remained unknown for decades.

Enter Karl Link, an agricultural chemist, working at the University of Wisconsin during the period after World War II when the promise of modern chemistry seemed limitless. From the photos and records, Link appears to have been a chemist with celebrity flair who put together a team devoted to isolating the active ingredient in moldy clover. Coumarin is a natural compound found in clover that imparts a sweet odor. When clover becomes moldy, fungi release an enzyme that converts coumarin to dicoumarol, which has anticoagulant properties. The active chemical moiety in dicoumarol was identified by Link's laboratory and later named warfarin (Coumadin). The chemical isolation effort, which took 7 years of laboratory persistence, was conducted at the Wisconsin Alumni Research Foundation, hence the name warfarin.

Coumadin was introduced in 1948 as a poison for rodents. In 1951 during the Korean war, a reluctant soldier deliberately took the rodent poison in a suicide attempt. When he was treated with vitamin K and survived, physicians quickly realized that, if dosed correctly, Coumadin could induce controlled and reversible anticoagulation. Not long afterward, in 1955, President Eisenhower suffered a myocardial infarction and was treated, in what we would now recognize as a therapy ahead of its time, with the new blood thinner. Coumadin had arrived.

Mechanism of action

Warfarin inhibits a vitamin K–dependent cyclic enzymatic pathway, which serves to attach carboxyl groups on glutamic acid residues of numerous coagulation factors (II, VII, IX, X, C, S, Z; see Fig. 2). γ-Carboxylation of these glutamic acid residues is a posttranslational processing step. Thus, the reversal of warfarin's effect by vitamin K does not require “resynthesis” of clotting factors (as is often misstated), but rather posttranslational modification of already synthesized proteins.

image

Figure 2. Mechanism of action of Coumadin.

Download figure to PowerPoint

Warfarin metabolism and personalized genetics

Since the initial report in 2005, several single-nucleotide polymorphisms (SNPs) found in either the vitamin K–epoxide reductase complex (VKORC1 gene) or the P450 hepatic drug-metabolizing enzyme (CYP2C9 gene) affect the dose of warfarin required for anticoagulation. For example, higher doses of warfarin are required among those who inherit the following SNPs in VKORC1: C at Position 1173 (within intron 1), A at Position 3730 (within the 3′ untranslated region), and G at Position –1639 (within the upstream promoter region). Lower doses of warfarin are required among individuals who inherit any of several CYP2C9 SNPs, which reduce metabolism of warfarin. Currently, it is felt that genetic variation in VKORC1 and CYP2C9 account for almost half of the variability observed in warfarin dosing.3

REVERSING WARFARIN

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Vitamin K: effective, inexpensive, and misunderstood

Vitamin K's essential role in blood clotting was discovered in studies done on chicks raised on a cholesterol-depleted diet. The vitamin was given the letter “K” for “Koagulation” and the work leading to its discovery was awarded a Nobel Prize. Vitamin K is an inexpensive, effective, and reliable reversal agent for warfarin. Two widely held clinical misconceptions have interfered with the effective use of vitamin K for warfarin-related bleeding. The first misconception is that vitamin K is slow to reverse warfarin. This largely results from observation of the effect of vitamin K on the international normalized ratio (INR) when vitamin K is administered subcutaneously. Because vitamin K1 is a fat-soluble compound, subcutaneous injection slows absorption due to its solubility in subcutaneous fat. Although commonly administered subcutaneously, this route of administration is the least effective for urgent reversal of warfarin. In contrast, as shown in Fig. 3, vitamin K effectively reverses the INR when given intravenously (IV) or orally.4-6

image

Figure 3. Time course of INR in response to different routes of administration of vitamin K. Data from Raj et al.,4Crowther et al.,5and Lubetsky et al.6(inline image) 1 mg subcutaneously; (inline image) 2.5 mg orally; (inline image) 1 mg IV.

Download figure to PowerPoint

A second clinical misconception is that IV vitamin K has a high likelihood of causing anaphylaxis. Although the mechanism of anaphylactic reactions to vitamin K is not fully understood, it is thought to be an idiosyncratic response to the vehicle (Cremophor EL) added to the preparation in order to solubilize vitamin K1 in an aqueous solution.7 Anaphylactoid reactions to vitamin K have been reported after oral and subcutaneous administration as well. The true incidence is unknown but is likely to be very low. For many years vitamin K has been routinely added to parenteral IV solutions and administered by IV drip to countless patients without reactions. The package insert recommends that IV vitamin K be given at a rate no greater than 1 mg/min. We instruct our hospital staff that when confronted with a need for reversal of warfarin that is sufficiently urgent to merit blood products, then the administration of IV vitamin K at a rate not exceeding 1 mg/min is appropriate medical care.

Plasma for reversal of warfarin

While vitamin K remains the specific antidote to warfarin, fresh-frozen plasma (FFP) or other forms of frozen plasma have traditionally been used for emergency reversal of warfarin. Emergency reversal is variously defined. In undoubtedly far too many cases, emergency reversal is not an emergency at all but rather reversal for the convenience of an inpatient physician wishing to perform an invasive procedure. In other cases, such as intracranial bleeding, rapid reversal of anticoagulation is justified and considered essential even though it has not been formally proven to change survival outcomes.

The INR has been the traditional measure of anticoagulation reversal. As shown in Fig. 4, the INR has a nonlinear relationship to the level of coagulation factors in the blood. The INR test is widely misinterpreted. A principal shortcoming of this test is that it is too “sensitive”—meaning that the INR value is “abnormal” even among patients with levels of clotting factors that are perfectly adequate for hemostasis. Physicians who claim that a patient has a “coagulopathy” as evidenced by an INR of 1.6 misunderstand this important detail. In fact, an INR of 1.6 is no more a measure of clinically impaired hemostasis than a platelet count of 140 × 103 (also outside the normal range) represents clinically important thrombocytopenia. Thus, therapeutic goals of normal INR values, or as we shall see below, study endpoints that target near normal INR values, are inappropriate and are at the heart of the most common misuses of FFP. Figure 4 demonstrates four additional points: 1) that standard anticoagulation (INR values of 2-3) corresponds to a rather narrow band of clotting factor concentrations; 2) that only modest increases in the levels of clotting factors are needed to restore factors to a concentration compatible with normal hemostasis; 3) that infusion of FFP has little effect on mildly prolonged INR values; and 4) that very large increases in factor levels—requiring large volumes of FFP—are required if one (incorrectly) wishes to achieve “normal” INR test results.

image

Figure 4. General relationship between the INR test or PT and the percentage of clotting factors in blood. The dotted line at 30% factors is a general threshold for adequate hemostasis. The hatched horizontal bar represents INR values that correspond to the zone of adequate factor levels. The dark horizontal bar represents INR values of anticoagulation. Arrows depict the effect of 1 to 2 units of FFP.

Download figure to PowerPoint

When FFP is used to reverse warfarin for serious bleeding events, vitamin K must also be given. Administered Factor (F)VII in FFP has a short (approx. 7 hr) in vivo half-life and F IX has a large volume of distribution. Thus, if vitamin K is not given, the levels of FVII and F IX from the administered FFP will decline. The failure to coadminister vitamin K in studies of warfarin reversal may have contributed to the reputation that FFP is not a reliable reversal agent. For example, a study performed at MGH is widely quoted as demonstrating that the time required to prepare and administer FFP is the principal reason that patients fail to promptly correct INR values.9 However, in this study, among those who failed to correct their INR at 24 hours, none received IV vitamin K. In fact, although all patients had warfarin-related intracranial hemorrhage, nearly one-quarter never received any form of vitamin K.

Table 1 shows the various forms of plasma available to blood transfusion services. The vitamin K–dependent factors are adequate in all frozen plasmas. Because thawed plasma has gained recent popularity in many hospitals, more data on the vitamin K–dependent factors (especially proteins C and S) in 5-day-thawed plasma would be welcome.

Table 1. Different forms of plasma*
FormFrozen withinAfter thaw, at 1-6°CCoagulation factorsFDA-licensed component
  • * 

    Source: Roback et al.8

FFP8 hr of collection24 hrStandard levelsYes
24-hr frozen plasma (FP24)24 hr of collection24 hrStandard levelsYes
Microwave thawed FFP or FP24Prepared from FFP or FP2424 hrStandard levelsYes
Thawed plasmaPrepared from FFP or FP245 daysReduced FVIII; little data on proteins C and SNo
Cryosupernatant plasmaPrepared from FFP or FP245 daysVery low FVIII; little data on proteins C and SYes
Liquid plasmaNever frozen5 days beyond expiration of whole bloodInadequate dataYes

Prothrombin complex concentrates: not all products are alike

In the past several years, prothrombin complex concentrates (PCCs) have taken the spotlight for warfarin reversal. The American College of Chest Physicians guidelines now suggest (not recommend) four-factor PCCs as the first choice for warfarin reversal in the setting of major bleeding.10 This is a Grade 2C recommendation meaning “weak” (Grade 2) based on “low evidence” (Grade C). However, most clinicians do not realize that four-factor PCCs are not available in the United States. Thus, understanding the composition of different PCC products is essential for hematologists and transfusion medicine physicians.

PCCs are broadly classified into three-factor and four-factor products (see Table 2). Four-factor PCCs actually contain six vitamin K–dependent factors (protein C and S are also present). In contrast, three-factor “PCCs,” more properly termed F IX concentrates, have therapeutically useful levels of only FII, F IX, and FX. In the United States, only three-factor PCCs (Bebulin VH and Profiline) are available, and neither is approved for warfarin reversal.

Table 2A. Factor levels (IU/mL) of several four-factor PCCs*
Product nameF IIF VIIF IXF XProtein CProtein S
  • * 

    Source: Kalina et al.11

Beriplex311629411827
Octaplex311622241224
S-TIM 4121181148
Kaskadil372823341215
Cofact30132326421
Table 2B. Factor levels (IU/mL) of F IX concentrates (“three-factor PCCs”)
Product nameF IIF VIIF IXF XProtein CProtein S
  • * 

    Product is not available in United States. See Kalina et al.11

  • † 

    Product information from Baxter Healthcare, September 2006, cited in Patanwala et al.12

  • ‡ 

    In-house testing of one lot of Profilnine conducted at MGH, Boston.

  • n/s = not stated.

Uman DI*28<0.1282195
Bebulin VH24-37<524-3724-37n/sn/s
Profilnine (n = 1)87nil6954nilnil

Given that FVII is the factor most severely depleted in warfarin-treated patients (because of its shortest in vivo half-life) and given that FVII is not present in three-factor PCCs, the reader might expect that three-factor PCCs would not adequately correct the hemostatic defect in warfarin-treated patients. This appears to be exactly the case. In an important study for US patients, Holland and colleagues13 reported on 40 patients who presented with an INR of greater than 5.0 (mean, approx. 8.8) and who were treated with three-factor PCC. Correction of the INR was compared to a historical control group (n = 42) who presented with an INR of greater than 5 (mean, 9.4) and who had been treated with FFP. Among the historical controls (of whom 70% received vitamin K), FFP lowered the INR to less than 3.0 in 63% of individuals. In the study group (of whom 40% received vitamin K), PCC at 25 IU/kg lowered the INR to less than 3.0 in 50% of individuals and PCC at 50 IU/kg lowered the INR to less than 3.0 in only 42% of individuals. In more than half of the PCC-treated patients, the clinical team decided to give supplemental FFP after the initial dose of PCC, after which the proportion of individuals achieving an INR less than 3.0 increased to 88%. The authors concluded that three-factor PCC by itself was not adequate to reverse warfarin among individuals who present with high INR values. A more recent article by Imberti and coworkers14 comes to a different conclusion suggesting that three-factor PCCs alone are adequate to reverse warfarin. The explanation for the discrepancy of conclusions was attributed to the fact that the patients in the study by Imberti and coworkers had much milder elevations of the INR before treatment,15 although it should also be noted that all patients in the study by Imberti and coworkers received vitamin K (10 mg IV), whereas only 40% of patients in the study by Holland and coworkers received some form of vitamin K.

Although the report of Holland and colleagues is retrospective, uses historical controls, and has a significant proportion of patients failing to receive vitamin K, the study is nonetheless important. Clinicians in the United States who read guideline documents that promote four-factor PCCs for reversal of warfarin are likely to request PCCs not realizing that four-factor PCCs are not yet available in the United States. If critically ill patients are to get the correct treatment, hematologists and transfusion medicine physicians in the United States need to educate clinicians regarding the factor content of current products. While at least one report has suggested mixing three-factor PCCs with recombinant activated (r)FVIIa,16 this approach should only be done with full institutional approval as it is clearly an unlicensed combination of two preparations both of which are not approved for this indication, and creates a mixture that adds an activated factor with a higher risk for serious thrombotic side effects. We do not use this approach at my institution.

FFP versus four-factor PCCs for reversal of warfarin

Four-factor PCCs have the obvious advantage of delivering a high concentration of factors in a smaller volume. The product volume is important especially given the likelihood of transfusion-associated volume overload17 when multiple units of FFP are given with the inappropriate target of a near normal INR value. Studies using a near-normal INR as an endpoint will almost certainly demonstrate toxicity of FFP even if they do not demonstrate greater efficacy of PCCs. Four-factor PCCs also have the advantage of more rapid delivery. As a result, proponents of PCCs would likely design studies using “time to INR correction” as an endpoint. An example is the small study of Boulis and colleagues,18 which examined the rate of INR correction in patients given PCC plus FFP versus FFP alone.

A direct comparison study of the safety profiles of FFP and PCC does not exist. While FFP carries a much higher chance of volume overload, especially if used without vitamin K and with inappropriate INR targets, PCCs are known to be thrombogenic.19 FFP is a much less expensive therapy costing perhaps one-tenth that of PCC. From a society perspective based strictly on cost-effectiveness, one might ask if four-factor PCCs are 10-fold more effective than FFP. Let us examine what we know.

Despite suggestions that four-factor PCCs are the treatment of choice for warfarin-related bleeding, no clinical study comparing FFP versus PCCs has used cessation of clinical bleeding or mortality as an outcome. Studies have used “time to correction of the INR” or “extent of correction of the INR” as a surrogate outcome of clinical effectiveness.12Table 3 summarizes four studies directly comparing FFP versus four-factor PCCs for reversal of warfarin. In 1992, Fredriksson and coworkers20 reviewed data on 17 patients with intracranial bleeding. Ten who received PCC lowered their INR from 2.83 to 1.22 in a mean of 4.8 hours whereas seven given FFP lowered their INR from 2.97 to 1.74 in a mean of 7.3 hours (p < 0.001). All received IV vitamin K. In 1997, Makris and colleagues21 reported retrospective data on INR corrections in 12 patients given FFP and 29 given some form of factor concentrate, but the patients had very different pretreatment INR values. The small retrospective study (n = 12) by Cartmill and coworkers22 found better and more rapid correction of the INR, but no difference in clinical outcomes, among patients treated with PCC and vitamin K compared with FFP and vitamin K. In 2010, Demeyere and colleagues23 reported the only prospective randomized controlled trial. Forty cardiac surgery patients on warfarin and undergoing cardiac surgery were randomly assigned to receive intraoperatively either a four-factor PCC (n = 18, two excluded) or FFP (n = 20). As expected, the median INR values were similar at baseline (2.7 for PCC and 2.6 for FFP). No patient received vitamin K. Patients assigned to FFP received 400 mL before bypass and 400 mL at the end for a total of approximately 800 IU of factors. However, patients randomly assigned to four-factor PCC received 40 mL of PCC before bypass and 40 mL at the end. Because the product has very high concentrations of factors (650 IU/mL FII, 280 IU/mL FVII, 565 IU/mL F IX, and 575 IU/mL FX), each patient received approximately 45,000 IU of each factor, or 50 times more factor than those assigned to FFP. At 15 minutes after bypass, INR values were 1.6 (PCC group) versus 2.3 (FFP group; p < 0.007) but at 60 minutes after bypass the INR values were 1.6 (PCC group) and 1.7 (FFP group; p = not significant). However, compared with the PCC group, a higher proportion of patients in the FFP group failed to achieve a target INR of less than 1.5. Despite the 50-fold difference in administered dose of factors, chest tube drainage at 1, 4, and 24 hours after surgery was not significantly different between the two groups. In this small study there was no measurable difference in clinical outcome (mortality or significant morbidity) between the two groups.

Table 3. Studies comparing four-factor PCC versus FFP for warfarin reversal
First author, yearDesignSample sizePatientsFindings
  1. ICH = intracranial hemorrhage.

Fredriksson, 199220RetrospectivePCC, n = 10ICHPCC: 2.83 [RIGHTWARDS ARROW] 1.22 @ 4.8 hr
FFP, n = 7FFP: 2.97 [RIGHTWARDS ARROW] 1.74 @ 7.3 hr
Makris, 199721RetrospectivePCC, n = 29ICHPCC: 5.8 [RIGHTWARDS ARROW] 1.3
FFP, n = 12FFP: 10.2 [RIGHTWARDS ARROW] 2.3
Cartmill, 200022RetrospectivePCC, n = 6ICHPCC: 4.86 [RIGHTWARDS ARROW] 1.32 @ 15 min
FFP, n = 6FFP: 5.32 [RIGHTWARDS ARROW] 2.30 @ 15 min
Demeyere, 201023Prospective, randomizedPCC, n = 18Cardiac surgeryPCC: 2.7 [RIGHTWARDS ARROW] 1.6 [RIGHTWARDS ARROW] 1.6
FFP, n = 20FFP: 2.6 [RIGHTWARDS ARROW] 2.3 [RIGHTWARDS ARROW] 1.7

rFVIIa

rFVIIa is not recommended as a solo agent to reverse warfarin. Although rFVIIa can shorten the INR, one would not expect a single-factor agent to restore a hemostasic defect resulting from depletion of four procoagulant factors. In fact, it does not. The failure of rFVIIa to reverse warfarin was first suggested in a rodent model where rFVIIa corrected the INR but did not arrest tail bleeding.24 In a separate study, Illanes and colleagues25 used a mouse intracranial hemorrhage model to study reversal of warfarin by rFVIIa, FFP, or four-factor PCC (100 IU/kg). Even when given an enormous dose of rFVIIa (10,000 µg/kg), mice given rFVIIa had intracranial hematoma volumes (14.7 ± 3.4 µL, n = 8) greater than those treated with FFP (8.7 ± 2.1 µL, n = 13) or PCC (7.5 ± 2.3 µL, n = 10).

Subsequently, Skolnick and coworkers26 gave warfarin to healthy volunteers and performed serial thigh punch wounds (5 mm diameter by 5 mm deep), measuring the time that each wound bled. Although the duration of bleeding was prolonged in all subjects as a result of warfarin, there was no effect on bleeding duration after injection of graded doses of rFVIIa compared with saline even when measured just 13 minutes after rFVIIa injection (see Fig. 5).

image

Figure 5. Failure of rFVIIa to arrest bleeding in normal volunteers taking warfarin. Punch biopsies of the thigh were taken at baseline (B0), after stable anticoagulation with warfarin (B1), 13 minutes after injection with rFVIIa (B2), and 5 hours after rFVIIa (B3). Data from Wojcik et al.27

Download figure to PowerPoint

FEIBA

FEIBA is licensed for use in persons with hemophilia with inhibitors. FEIBA contains activated factors and so is more likely to produce unwanted thrombosis than other agents. The product information plainly states that FEIBA “is contraindicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.” A retrospective study (which carries underestimation of adverse events) comparing outcomes in 72 patients receiving FEIBA for warfarin reversal with 69 patients receiving FFP found no improvement in clinical endpoints in those treated with FEIBA but found that 7% experienced adverse events potentially related to FEIBA.27 Overall survival was 88.2% among those treated with FFP and 77.8% among those receiving FEIBA (p = 0.12).

Current recommendations

American readers interested in recent guideline documents regarding warfarin reversal are invited to review the recent publication by the American College of Chest Physicians10 or the American Society of Hematology at http://www.hematology.org/Practice/Guidelines/2934.aspx.

NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

During the past year, several new oral anticoagulants have been licensed for use. These drugs are being positioned as the first alternatives to warfarin in nearly a half-century and fall into two general classes: direct thrombin inhibitors or inhibitors of FXa (see Table 4). Dabigatran etexilate (Pradaxa) is approved in the United States for stroke prevention in patients with nonvalvular atrial fibrillation. Rivaroxaban (Xarelto) is approved in the United States for prevention of venous thromboembolism after orthopedic surgery and for stroke prevention in atrial fibrillation. Apixaban (Eliquis) is expected to be approved for stroke prevention.

Table 4. New oral anticoagulants*
FeatureDabigatranRivaroxabanApixaban
  • * 

    Data from Bauer.2

MechanismDirect thrombin inhibitorDirect FXa inhibitorDirect FXa inhibitor
Molecular weight628436460
ProdrugYesNoNo
Peak action (tmax)1-3 hr1-3 hr1-3 hr
Elimination half-life (t1/2)12-17 hr7-11 hr9-14 hr
Renal clearance80%67%25%
Protein binding35%92%-95%84%
AntidoteNoNoNo

It is widely quoted that the pivotal trials for the new anticoagulants have shown them to be safer than warfarin—with fewer bleeding events and fewer fatal bleeding events. The magnitude of the difference is worth examining. In the RELY trial28 the rate of major bleeding was not statistically different—3.32% in the dabigatran group versus 3.57% in the warfarin group (relative risk, 0.93; 95% CI, 0.81-1.07; p = 0.31). The rate of life-threatening bleeding was lower in the dabigatran group (1.49%) compared with warfarin group (1.85%, p = 0.03), but the overall rate of death from any cause was not statistically different (3.64% vs. 4.13%, p = 0.051). Stronger significance was seen in the higher rate of major gastrointestinal bleeding with dabigatran (1.56%) compared with warfarin (1.07%; relative risk, 1.48; 95% CI, 1.18-1.85; p = 0.001). Comparisons were slightly more favorable for the new drug in a separate study of warfarin versus apixaban.29 More importantly, such data fail to recognize that medication trials require strict enrollment criteria that exclude patients who are more likely to have adverse effects from the study drug. For example, the dabigatran trial referred to above excluded patients with an increased risk of hemorrhage, a creatinine clearance of less than 30 mL/min, or active liver disease. However, once approved, medications may be used by patients with greater risks for bleeding. Thus, the true incidence of bleeding complications after licensure is expected to be higher than that observed in studies. Indeed early reports suggest unexpectedly high bleeding rates with dabigatran among elderly patients with impaired renal function.30

STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

A few studies, summarized below, have investigated reversal agents for the new oral anticoagulants (see Table 5). It is very important to recognize that no study in humans has evaluated any reversal agent using a clinical bleeding endpoint. One human study did report the effect of PCCs on the INR and activated partial thromboplastin time (aPTT).31 The other studies have used animal models, and most have been presented only in abstract form. Readers should note that animals infused with human blood factors may have a xenoprotein inflammatory response that enhances hemostasis in a manner not seen when humans receive human factors. Thus, studies involving xenotransfusions should be regarded as very preliminary and insufficient evidence upon which to make policy decisions.

Table 5. Studies investigating reversal of new oral anticoagulants
Product testedDabigatranRivaroxabanApixaban
  • * 

    Coagulation tests = PT, aPTT, thrombin time, dilute thrombin time, ecrine clotting time.

  • † 

    PT, thrombin generation, inhibition of Xa activity.

  • ‡ 

    PT, aPTT, ecarin clotting time, thrombin time, endogenous thrombin production.

  • ICH = intracranial hemorrhage.

FFPICH model (mouse)NoNo
rFVIIaICH model (mouse)Coagulation tests (rat)No
Tail bleeding and aPTT (rat)PT and bleeding time (baboon)
Tail bleed and coagulation tests (rat)* 
Four PCCICH model (mouse)Coagulation tests (human)No
Tail bleed and coagulation tests (rat)*
Coagulation tests (human)
FEIBATail bleeding and aPTT (rat)PT and bleeding time (baboon)No
Tail bleed and coagulation tests (rat)*
Three PCCNoNoNo

Mouse intracranial hemorrhage and tail vein bleeding model

Zhou and colleagues32 studied the effect of mouse FFP, a four-factor PCC, or rFVIIa in a mouse model of intracranial hemorrhage. The authors included employees of the company that makes dabigatran. Mice were given either 4.5 or 9 mg/kg dabigatran and then central nervous system bleeding was induced by striatal injection of collagenase. Thirty minutes later, one of four IV treatments was given: 200 µL of saline, 200 µL of FFP (equivalent to 2-3 units) prepared from EDTA-anticoagulated blood of other mice, high-dose human four-factor PCC (100 IU/kg), or rFVIIa at an enormous dose (8000 µg/kg). As judged by brain cryosections, hematoma volume was significantly smaller in the mice treated with PCC or FFP compared with saline, but was not smaller compared with saline in mice treated with rFVIIa. In separate experiments, tail vein bleeding time was significantly reduced by injection of 100 IU/kg of four-factor PCC but not by injection of either 50 or 25 IU/kg. Neither FFP nor rFVIIa was tested in the tail vein bleeding assay. The most reliable conclusion from this study is that rFVIIa, given in very high doses, had no effect.

Rat models

In 2007, Tinel and Perzborn33 reported in abstract form (full report never published) studies on the use of rFVIIa (at 400 µg/kg) to reverse rivaroxaban (2 mg/kg) in rats. After an unstated time period following IV rivaroxaban, animals received rFVIIa and 1 minute later were tested for coagulation. The prothrombin time (PT) increased from 150 to 975 seconds with rivaroxaban and partially corrected to 543 seconds after rFVIIa. Thrombin generation decreased from 51,616 to 36,314 with drug and partially corrected to 42,813 with rFVIIa. Inhibition of Xa was nil at baseline, increased to 774% with the Xa inhibitor drug, and failed to improve with rFVIIa (812% inhibition). The study showed no evidence for direct reversal of Xa inhibition from even 400 µg/kg rFVIIa.

In 2008, van Ryn and coworkers34 reported in abstract form attempts to reverse dabigatran in rats with either FEIBA or rFVIIa. Rats (number not stated) were anticoagulated with a 25-minute infusion of dabigatran. Animals were injected with either FEIBA (100 IU/kg) or rFVIIa (1000 µg/kg) and then, after the procoagulant, the tail was cut to measure the duration of bleeding. The authors reported shortened tail bleeding times but no effect on the aPTT. The study design is so flawed to make conclusions very difficult.

In 2011, van Ryan,35 who is an employee of the company that makes dabigatran, reported a more detailed study in rats. Animals were given 30 mg/kg dabigatran by gavage. Forty-five minutes later, after anesthesia and IV line placement, groups of rats (n = 3-6) were given Beriplex (35 IU/kg), Octaplex (40 IU/kg), FEIBA (100 IU/kg), or rFVIIa (stated as 0.5 µg/kg but probably 500 µg/kg). Baseline cut tail bleeding time (171 sec) increased to 495 seconds with dabigatran. The authors reported that prolonged cut tail bleeding times were reversed within 5 minutes with each of the procoagulants. However, none of the procoagulants corrected laboratory assays of hemostasis including PT, aPTT, thrombin time, dilute thrombin time, or ecrine clotting time. Data are not given in the published abstract.

Baboon study with rivaroxaban

A 2008 abstract (never published in full manuscript form) studied the potential for FEIBA or rFVIIa to reverse rivaroxaban in a baboon model.36 After baseline bleeding time and PT were measured, juvenile baboons (n = 7) were given rivaroxaban over 60 minutes and then given an infusion of FEIBA (50 IU/kg). After giving rivaroxaban, the median bleeding time (relative to baseline) increased to 2.02, and 20 minutes after FEIBA was 1.65. The PT after rivaroxaban increased to 3.04 ± 0.43 times baseline, and 20 minutes after FEIBA was 2.28 ± 0.29-fold above baseline. The same study model was repeated (n = 7) using rFVIIa (210 µg/kg) as the reversal agent. Bleeding times increased to 2.54-fold above baseline with rivaroxaban and were 1.96 above baseline after rFVIIa; PT values increased to 3.17 ± 0.42-fold above baseline after rivaroxaban and were 2.48 ± 0.49-fold above baseline after rFVIIa.

One study in humans

One study in humans has examined the effect on coagulation test results of four-factor PCCs administered to normal volunteers receiving dabigatran or rivaroxaban. Eerenberg and coworkers31 reported results on 12 healthy males who received dabigatran (150 mg bid) followed by either a single bolus of four-factor PCC (Cofact, 50 IU/kg) or saline control. After a washout period, the experiment was repeated using anticoagulation with rivaroxaban (20 mg bid). Dabigatran increased the aPTT from 33.6 ± 3.3 to 59.4 ± 15.8 seconds. Infusion of PCC had no reversal effect (aPTT after PCC was 70.3 ± 15.1, p = 0.2). PCC also had no reversal effect on prolonged ecarin clotting time or thrombin time produced by dabigatran. In contrast, rivaroxaban increased the PT (from baseline 12.3 ± 0.7 to 15.8 ± 1.3) which returned to near baseline (12.8 ± 1.0) after PCC infusion. Rivaroxaban also inhibited endogenous thrombin production, which corrected with infusion of PCC. This study found completely different responses to PCC infusion, depending on which oral anticoagulant was given. This study, using normal volunteers, was not designed to address bleeding outcomes nor the effect of PCC on markedly elevated anticoagulant levels.

Anecdotal case reports in humans

We can anticipate a large number of anecdotal case reports of attempts to reverse the new oral agents. For example, Warkentin and colleagues37 reported a single case report of excessive postoperative bleeding in a cardiac patient on dabigatran. Although the authors claim that the patient responded to rFVIIa, the data in the report show no improvement in the thrombin time in response to rFVIIa and improvement after dialysis. In another example, an elderly man taking dabigatran fell and suffered an intracranial bleed that was unresponsive to rFVIIa and proved fatal.38 A registry in New Zealand reported a group of patients taking the new oral agents who experienced bleeding that was poorly controlled.39

Management of bleeding in patients taking new oral anticoagulants

Strategies to address bleeding among patients taking the new oral anticoagulants are in flux. Readers should expect a plethora of guidelines and advice, with content that may vary depending on the perspective of the advisor. Cases of deliberate or accidental drug overdose will be treated with gastric lavage and oral charcoal.40 Because the drugs are excreted by the kidneys, bleeding episodes are likely to accompany new-onset renal insufficiency. Dialysis41 or charcoal hemoperfusion40 may be tried in some cases to remove dabigatran. Because rivaroxaban is highly protein bound, dialysis is less likely to be effective and plasma exchange (currently untested as a reversal strategy) might be better suited to remove drug and replace clotting factors.

For patients with preserved renal function, the drug effect will clear within hours and the safest treatment strategy is likely to be supportive care with red blood cell transfusions rather than injections of procoagulants into patients who had reason to be treated with anticoagulants. Local hemostatic measures may prove most effective and least toxic. While there are no clinical studies as yet, the use of high-dose topical thrombin at the site of bleeding would be expected to overwhelm the effect of the new anticoagulants without risking a systemic procoagulant effect. Indeed, this new class of nonreversible systemic anticoagulants may serve to reteach practitioners that not all bleeding should be addressed through IV infusions and that local bleeding is often best treated with local measures.

CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES

Only time will tell if the new alternatives to warfarin represent a substantial advance of safety and efficacy. However, it is certain that they are an enormous financial opportunity for the pharmaceutical industry. Physicians evaluating published reports and receiving educational material will want to pay particular attention to conflicts of interest. In particular, we should understand that the pharmaceutical companies that market anticoagulants have a very strong incentive for clinicians to believe that some form of “reversal agent” exists. Otherwise, physicians may be reluctant to prescribe the newer anticoagulants. We can also expect that, on the horizon, true reversing agents will be introduced. One promising line of development is a mutated form of FXa, which has no in vivo effect but which can form complexes with (and thus neutralize) Xa inhibitor drugs.42 The ultimate goal for society is the development of an oral anticoagulant that can be taken once a day, that will effectively reduce the risk of stroke or thrombosis in patients with a wide range of thrombophilic disorders, that is inexpensive and nontoxic, and that can be promptly reversed should bleeding occur. Sort of sounds like warfarin, doesn't it?

REFERENCES

  1. Top of page
  2. Abstract
  3. ANTICOAGULANT USE ON THE RISE
  4. WARFARIN ANTICOAGULATION
  5. REVERSING WARFARIN
  6. NEW ORAL ANTICOAGULANTS: CONVENIENT TO USE BUT NOT REVERSIBLE
  7. STUDIES EXPLORING “REVERSAL” OF NEW ORAL ANTICOAGULANTS
  8. CONCLUSION: BE SKEPTICAL OF UPCOMING CLAIMS REGARDING REVERSAL AGENTS
  9. CONFLICT OF INTEREST
  10. REFERENCES
  • 1
    Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood 2011;117:6091-9.
  • 2
    Bauer KA. Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. J Thromb Haemost 2011;9 Suppl 1:12-9.
  • 3
    Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90:625-9.
  • 4
    Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med 1999;159:2721-4.
  • 5
    Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C, Venco A, Ageno W. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med 2002;137:251-4.
  • 6
    Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003;163:2469-73.
  • 7
    Fiore LD, Scola MA, Cantillon CE, Brophy MT. Anaphylactoid reactions to vitamin K. J Thromb Thrombolysis 2001;11:175-83.
  • 8
    Roback JD, Grossman BJ, Harris T, Hillyer CD, editors. Technical manual. 17th ed. Bethesda (MD): American Association of Blood Banks; 2011. p. 275.
  • 9
    Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006;37:151-5.
  • 10
    Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH; American College of Chest Physicians. 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 Suppl:e152S-84S.
  • 11
    Kalina U, Bickhard H, Schulte S. Biochemical comparison of seven commercially available prothrombin complex concentrates. Int J Clin Pract 2008;62:1614-22.
  • 12
    Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 2011;45:990-9.
  • 13
    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.
  • 14
    Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, D'Incà M, Gnani MC, Mari E, Ageno W. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148-55.
  • 15
    Makris M, Van Veen JJ. Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 2011;9:117-9.
  • 16
    Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg 2012;116:491-7.
  • 17
    Li G, Rachmale S, Kojicic M, Shahjehan K, Malinchoc M, Kor DJ, Gajic O. Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients. Transfusion 2011;51:338-43.
  • 18
    Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999;45:1113-8; discussion 1118-9.
  • 19
    Dentali F, Marchesi C, Pierfranceschi MG, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011;106:429-38.
  • 20
    Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992;23:972-7.
  • 21
    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.
  • 22
    Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000;14:458-61.
  • 23
    Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang 2010;99:251-60.
  • 24
    Dickneite G. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res 2007;119:643-51.
  • 25
    Illanes S, Zhou W, Schwarting S, Heiland S, Veltkamp R. Comparative effectiveness of hemostatic therapy in experimental warfarin-associated intracerebral hemorrhage. Stroke 2011;42:191-5.
  • 26
    Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010;116:693-701.
  • 27
    Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med 2009;2:217-25.
  • 28
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
  • 29
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Wallentin L, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
  • 30
    Harper PY, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864-6.
  • 31
    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.
  • 32
    Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S, van Ryn J, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011;42:3594-9.
  • 33
    Tinel HH, Perzborn E. Recombinant factor VIIA partially reverses the anticoagulant effect of high-dose rivaroxaban—a novel, oral, direct factor XA inhibitor—in rats [abstract]. J Thromb Haemost 2007;5 Suppl 2:P-W-652.
  • 34
    van Ryn J, Ruehl D, Priepke H, Hauel N, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran by recombinant factor VIIa or activated prothrombin complex concentrate [abstract]. Haematologica 2008;93 Suppl 1:148.
  • 35
    van Ryn J, Schurer 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 [abstract]. Blood 2011;118:2316.
  • 36
    Gruber A, Marzec U, Buetehorn U, Hanson S, Perzborn E. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates [abstract]. Blood 2008;112:3825.
  • 37
    Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012;119:2172-4.
  • 38
    Garber ST, Sivakumar W, Schmidt RH. Neurosurgical complications of direct thrombin inhibitors-catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran. J Neurosurg 2012 Mar 6. [Epub ahead of print]
  • 39
    Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864-6.
  • 40
    van Ryn J, Sieger P, Kink-Eiband M, Gansser D, Clemens A. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro [abstract]. Blood 2009;114:1065.
  • 41
    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.
  • 42
    Lu G, DeGuzman F, Lakhotia S, Hollenbach SJ, Phillips DR, Sinha U. Recombinant antidote for reversal of anticoagulation by Factor Xa inhibitors [abstract]. Blood 2008;112:983.