clinical experience with oral versus intravenous vitamin k for warfarin reversal

O R I G I N A L A R T I C L E

Clinical experience with oral versus intravenous vitamin K forwarfarin reversal_3755 1..8

Robert Meehan, Maria Tavares, and Joseph Sweeney

BACKGROUND: Reversal of warfarin with plasmaaccounts for a large amount of fresh-frozen plasmatransfused in the United States. The use of vitamin K isan alternate strategy.STUDY DESIGN AND METHODS: Records of vita-min K prescriptions for warfarin reversal were examinedand recipients identified where data were available ondosage, route of administration (oral [PO] and intrave-nous [IV]) and the availability of both pre- and postad-ministration international normalized ratio(s) (INRs).RESULTS: A total of 135 administration events wereevaluated: 81 PO and 54 IV. The median (range) pread-ministration INRs were 5.8 (1.9-16.5) versus 5.0(1.4-16.5; p = 0.61) and the median (range) for thepostadministration INRs were 2.4 (1.0-10.4) and 2.1(1.2-8.2; p < 0.01) for the PO and IV routes, respec-tively. The median (range) doses were 2.5 (1-10) and2.0 (1-10) mg for PO and IV, respectively (p < 0.01). Atotal of 44% of the IV vitamin K group achieved an INRof 2 or less within 12 hours versus 14% for the POroute (p < 0.01). In multilinear regression the preadmin-istration INR (r = 0.14, p < 0.01) and time after adminis-tration (r = -0.05, p < 0.01) were independent variablesinfluencing the postadministration INR but the doseadministered (r = 0.09, p = 0.07) was not.CONCLUSION: Vitamin K needs to be given IV ifurgent partial correction (<12 hr) of warfarin isrequired. No influence of dose administered in therange 1 to 10 mg on the postadministration INR wasobserved.

Vitamin K antagonists have been used as antico-agulants since the 1940s and are of benefit inthe primary prophylaxis of thromboembolicdisease in atrial fibrillation and prosthetic heart

valves and in the secondary prophylaxis of venous throm-boembolism (VTE).1-3 Both coumarins and indandionesare available in Europe, but in the United States, only acoumarin compound (warfarin) is available. Warfarin isthe most commonly prescribed anticoagulant in theUnited States, with approximately 31 million prescriptionsissued in 2004.4 Despite decades of experience with war-farin, it remains a difficult drug to control therapeuticallybecause of its narrow therapeutic index and it remainsprominent on the list of medications responsible foradverse drug events presenting to emergency rooms.5,6

Bleeding is the most common adverse event associ-ated with warfarin and hence periodic testing is routinelyperformed to prevent excess anticoagulation. The pro-thrombin time and its derivative, the international nor-malized ratio (INR), is the coagulation test that is mostcommonly used for this purpose.7-9 The target INR foratrial fibrillation and VTE is 2.5 and for prosthetic heartvalves 3.0; however, the acceptable ranges are 2.0 to 3.0and 2.5 to 3.5, respectively.3 The time within this range canbe measured using an index, called the Rosendaal index,and it is not uncommon for this index in any one patientor groups of patients to be less than 60%, indicatingconsiderable time outside of the accepted range.6,10 Thisis because the in vivo effect of this drug shows great

ABBREVIATIONS: aPTT = activated partial thromboplastin

time; INR = international normalized ratio; PO = oral;

VTE = venous thromboembolism.

From the Blood Bank and Department of Medicine, Roger Will-

iams Hospital, Providence, Rhode Island.

Address reprint requests to: Joseph Sweeney, MD, FACP,

FRCPath, Roger Williams Hospital, 825 Chalkstone Avenue,

Providence, RI 0290; e-mail: [email protected].

Received for publication August 8, 2011; revision received

May 4, 2012, and accepted May 8, 2012.

doi: 10.1111/j.1537-2995.2012.03755.x

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intraindividual and interindividual variation, which isknown to be caused by genetic and ethnic differences insusceptibility to drug effect11-13 or the effects of age,12

dietary factors, or concomitant use of other drugs orherbal supplements.14 When the INR exceeds 3.5, the riskof bleeding begins to increase exponentially6,15 and rever-sal is required either by temporary discontinuation ofwarfarin16,17 or by the administration of vitamin K,17,18

depending on the INR value.In certain clinical scenarios, as in cases where clinically

significant bleeding is occurring or an immediate invasiveprocedure is required, patients with high INRs require morerapid reversal of the vitamin K antagonists and eitherplasma19 or prothrombin complex concentrates19,20 orboth21 are used, since there is a known time delay betweenthe administration of vitamin K and the reversal of the war-farin effect.22 A recent report shows that this scenarioaccounts for a large amount of the total plasma transfusedin the United States23 and elsewhere.24 While the use ofplasma in some of these settings, such as intracranialbleeding or emergency surgery, is appropriate,25 other sce-narios in which the bleeding is clinically less (not requiringred blood cell [RBC] transfusion in a hemodynamicallystable patient) or there is an urgent, but not immediate,need for a procedure can allow for the use of vitamin K toreverse the warfarin effect and thus avoid plasma transfu-sion.22,25 In the period 2002 to 2010, a practice was initiatedat our hospital to discourage plasma use in such cases andto actively promote the use of vitamin K.26 It was observedthat clinicians prescribed varying doses of vitamin K andfrequently prescribed vitamin K by mouth rather thanintravenously (IV) partly because of exaggerated concernsregarding the potential for an anaphylactic reaction27 andpartly on the erroneous belief that the reversal effect wouldhave a similar time course using either route.28,29 Previousstudies have reported on the use of vitamin K in the contextof prospective controlled studies or small retrospectiveobservational studies with minimum variation in dosesadministered or a single route of administration studied.The purpose of this study was to report on observed varia-tion in practice within a single institution, which is morelikely to represent actual clinical practice.

MATERIALS AND METHODS

The study was approved by the institutional reviewboard of Roger Williams Hospital (Providence, RI). RogerWilliams Hospital is a 220-bed tertiary care university-affiliated teaching hospital with residency training pro-grams in internal medicine and subspecialty fellowshipsin hematology-oncology, pulmonary-intensive care unit,rheumatology, endocrinology, and surgical oncology.Most admissions are general medical patients. It has anemphasis on oncology and is the site of the only bonemarrow transplant center in the state. The pharmacy was

queried for prescriptions of vitamin K by any route ofadministration over the 14-month period between August2009 and October 2010. This period was arbitrarily chosenas the program was well established at this time and largedecreases in plasma use had been observed. Records wereexamined for patients on warfarin and events consideredeligible for analysis were vitamin K administrations inwhich a preadministration INR was available; at least onepostadministration INR was obtained within a 48-hourperiod; and the dose, time, and route of administrationknown. For each eligible event, the age, sex, platelet (PLT)count, activated partial thromboplastin time (aPTT; whereavailable), reason for warfarin use, time interval from theavailability of the preadministration INR test result to thetime of vitamin K administration (lag time), time intervalbetween the administration of vitamin K, and the postad-ministration INR (post–vitamin K administration time)were recorded. The reason for vitamin K administration(active bleeding, invasive procedure, or correction of asupratherapeutic INR) was recorded and the change inINR (DINR) was calculated by subtracting the postadmin-istration INR from the preadministration INR.

Data were entered into a computer spreadsheet(Excel, Microsoft Corp., Redmond, WA), imported into astatistical software application (Epistat, Richardson, TX),and summarized as descriptive statistics. Eligible eventswere analyzed as a whole group or separated into orallyadministered (PO) vitamin K and IV vitamin K. Statisticalanalysis was performed by Mann-Whitney U tests, chi-square tests, or multilinear regression, as appropriate. Thecorrelation coefficient in univariate analysis was Pearson’scoefficient. Significance was defined as a p value of lessthan 0.05.

RESULTS

A total of 1276 vitamin K administrations occurred duringthis period, 1083 doses PO and 193 doses IV. Oral doses of5 or 10 mg were administered as 5-mg whole tablets ofphytonadione (Aquamephyton). Oral doses of 1, 2, or2.5 mg were administered by drawing up 0.1, 0.2, or0.25 mL of the liquid formulation of vitamin K (10 mg/mL) using a tuberculin syringe and giving this by mouth. Atotal of 882 of these 1083 oral doses were given prophylac-tically to bone marrow transplant patients and of theremaining 201 doses, 81 were eligible for inclusion. IV vita-min K was administered in an infusion containing 50 mLof either 5% dextrose or saline over 30 minutes. Of the 193IV administrations, however, only 54 were eligible forinclusion. Ineligibility for inclusion was based on theabsence of a repeat INR within 48 hours of vitamin Kadministration. The 135 patients were mostly elderly witha median age of 79 (range, 32-95) years and consisted of 68males and 67 females. The majority (114/135, 85%) weretaking warfarin for atrial fibrillation. Sixteen (12%) were

MEEHAN ET AL.

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taking warfarin for secondary thromboprophylaxis of VTE,three (2%) for secondary thromboprophylaxis of arterialthrombosis, and only two (1%) for valve prosthesis. Vita-min K was administered on account of an anticipated pro-cedure in 57 cases (42%), to reverse a high INR in 36 cases(27%), and to manage bleeding in 42 cases (31%). Themedian preadministration INR was 5.2 (range, 1.4-16.5)and the median dose was 2.5 mg (range, 1-10 mg). Datawere available for the aPTT for 82 patients: the medianaPTT was 54 seconds (normal, 22-33 sec) and the aPTTcorrelated with the preadministration INR (r = 0.44,p < 0.01). The mean PLT count was 242 ¥ 109/L (range,5 ¥ 109-698 ¥ 109/L). All but one patient had a PLT count ofmore than 50 ¥ 109/L. The median time from INR resultavailability to vitamin K administration (lag time) was 5.5hours (range, 0-22 hr) indicating considerable delay inresponse to test result availability in some cases. Forty-twounits of RBCs were given to 32 of the patients and one PLTdose was administered to a single patient with a PLT countof 5 ¥ 109/L.

The patient population was divided into the PO andIV administration groups and the data are shown inTable 1. Ages, sex, and preadministration INRs weresimilar in both groups but the postadministration INRswere significantly less in the IV group consistent with amore rapid onset of action of the IV formulation. This wasevident despite a shorter time interval in the collection ofthe subsequent sample for INR measurement and that thedose of IV vitamin K was less. Achievement of a docu-mented INR of less than 2 differed between the groups butnot an INR of less than 1.5 within 24 hours. Fifty-one of the54 patients in the IV group and 68 of the 81 patients in thePO group had a second INR within 48 hours and themedian times and INRs are illustrated in Fig. 1 emphasiz-ing the ability of IV vitamin K to more rapidly achievereversal of the warfarin effect. Consistent with this, a largerfraction of the actively bleeding patients received IV vita-min K and a larger fraction of the patients treated withvitamin K for a supratherapeutic INR received PO vita-min K. No difference was observed in the patients being

prepared for a procedure. Although the data for aggregateresponse is seen in Fig. 1, interpatient differences in therate of response may occur. Ten patients in each of the twogroups were chosen to represent a wide range of pretreat-ment INRs all of whom had at least two INRs within a48-hour period to illustrate the difference in rate ofresponse. This difference is shown in Fig. 2. The morerapid response in the IV group is again shown but someintersubject variation is evident in the early hours aftervitamin K administration by either route. However,approximately 8 hours after IV administration and 24hours after PO administration the postadministrationINRs converge, allowing some degree of predictability ofthe postadministration INR after these time intervals.

As actively bleeding patients may differ from non-bleeding patients, the population was separated into the

TABLE 1. Characteristics and responses of the patient population separated by route of administration*Characteristics Oral (n = 81) IV (n = 54) p value

Age (years) 80 (43-94) 76 (32-95) 0.53% males 46 57 0.25Preadministration INR 5.8 (1.9-16.5) 5.0 (1.4-16.5) 0.61Postadministration INR 2.4 (1.0-10.4) 2.1 (1.2-8.2) <0.01Dose (mg) 2.5 (1.0-10.0) 2.0 (1.0-10.0) <0.01Sample time after vitamin K administration (hr) 13.25 (1.25-40.75) 6.5 (0.5-25.25) <0.01Documented INR � 2.0 within 12 hr 14% 44% <0.01Documented INR � 1.5 within 24 hr 67% 77% 0.87Acute bleeding 23% 43% 0.03Warfarin reversal before procedure 42% 43% 0.92Correction of supratherapeutic INR 35% 14% 0.02

* Data are reported as median (range).

Fig. 1. Response to administration of vitamin K in PO-treated

(n = 51) and IV-treated (n = 68) patients. The posttreatment

INR 1 and the posttreatment INR 2 are the first and second

specimens collected after drug administration, respectively.

Data points are the medians and error bars represent the

interquartile range.

WARFARIN REVERSAL WITH VITAMIN K


bleeding and nonbleeding subpopula-tions and stratified by route of vitamin Kadministration. These data are shown inTable 2. With the obvious exception ofthe fraction of patients transfused, therewere few differences between thebleeder and nonbleeder groups. Impor-tantly there was no indication of a differ-ence in dose administered, responsetime (time interval between the time ofresult available and the time of adminis-tration of vitamin K), and the timing ofsample collection for postadministra-tion INR testing. In view of the failure toobserve any clear bias for higher doses ofvitamin K to be administered IV for thegroup as a whole or for the bleeding sub-population, a multilinear regressionanalysis was performed using the post-administration INR as the outcome vari-able and the preadministration INR,time to sample collection after vitamin Kadministration, and dose as input vari-ables. Both preadministration INR andsample collection time were indepen-dent variables determining the post-administration INR but the dose wasnot. This lack of relationship betweendose and change in the INR (DINR) isshown as a bubble graph in Fig. 3. As isevident by the diameters of the bubbles,there were a large number of prescrip-tions in the dosage range from 1 to10 mg. There is no indication that doseshigher than 1 mg influence the DINR.

DISCUSSION

Our data show considerable variation inresponse time to test result availability,dosage, and route of administration of

Fig. 2. Representative time series of 10 patients who received either vitamin K PO or

vitamin K IV over a large range of preadministration INRs and for whom at least two

postadministration INRs were available.

TABLE 2. Response to vitamin K in the actively bleeding and nonbleeding patients separated by route ofvitamin K administration*

Clinical data

Bleeders Nonbleeders

PO (n = 19) IV (n = 23) PO (n = 62) IV (n = 31)

Preadministration INR 4.0 (2.6-16.5) 5.2 (2.2-16.5) 6.3 (1.9-16.5)† 4.0 (1.4-16.5)Postadministration INR 2.0 (1.4-3.9) 2.2 (1.3-8.2) 2.7 (1.0-10.0)† 2.0 (1.2-3.9)‡Sample time after vitamin K (hr) 11 (2.5-21) 6.4 (1-24) 14 (1.25-41) 7 (0.5-25)‡Lag time in response (hr) 6 (0-15) 4.8 (0.25-22.5) 5.4 (0-21) 5 (0.5-20.5)Dose (mg) 5 (1-10) 2 (1-10) 2.5 (1-10) 2 (1-10)‡RBCs units transfused 15/19 19/23 1/62§ 0/31§

* Data are reported as median (range).† p < 0.05 between bleeders versus nonbleeders given PO vitamin K.‡ p < 0.05 between PO versus IV nonbleeders.§ p < 0.05 between bleeders versus nonbleeders given IV vitamin K.

MEEHAN ET AL.


vitamin K, which we could not clearly relate to the clinicalindication. This represents the largest reported observa-tional study in which there is a wide range in the pretreat-ment INRs for both oral and IV vitamin K and may bereflective of common practice indicating that misinforma-tion regarding dosage and route of administration may beprevalent and that considerable education on vitamin Ktherapy to reverse warfarin would be appropriate.

There have been two reports comparing oral versus IVvitamin K for warfarin reversal but no dose stratificationthat would allow a clear dose determination for any givenINR. One report showed better correction with “high-dosevitamin K” (1-10 mg) compared to “low-dose IV vita-min K” (0.5-1.0 mg) and the high dose was superior to oralvitamin K (mean oral dose, 3.8 mg).28 The other reportcompared different oral formulations with a single IV for-mulation. The IV formulation (2 mg) was superior in effi-cacy to any of the oral formulations (1-5 mg) at both 4 and24 hours after administration.29 An additional retrospec-tive observational study on the efficacy of IV vitamin K forwarfarin reversal showed that doses of more than 1 mgresulted in a shorter time interval to achieve a target INRof 1.4 or have a procedure performed than doses of notmore than 1.0 mg.30 A recent large prospective single armstudy (n = 178) using a fixed IV dose of 3 mg to partiallyreverse warfarin before a procedure showed that 94% ofpatients achieved an INR of less than 1.5 within 18 hours.The range of INRs in this report was not wide, however (1.5to 4.6).31 Recommendations for warfarin reversal from theAmerican College of Chest Physicians recommend an oraldose for nonbleeding patients only if the INR exceeds 10and IV dosing for bleeding patients either at a dose of 5 or10 mg.32 Based on these reports, the IV route has a morerapid onset of action and a minimal dose of 1 mg is appro-priate but it remains unclear whether higher doses byeither route are more efficacious.

These data from controlled studies are consistentwith our own data. A strength in our study is that theobservations include patients with a wide range in pre-treatment INRs and are more likely to be representative ofcommon practice. Furthermore, more than a single timepoint was available for a majority of the patients, whichallowed the construction of time series plots. These wereuseful as interpatient variation in response to vitamin K isevident in the early hours after vitamin K administrationbut approximately 12 hours after IV vitamin K and 24hours after oral vitamin K, these interpatient differenceswere minimal regardless of the pretreatment INR, allow-ing some degree of predictability of the posttreatment INRat these time points (Fig. 2). A limitation is the possiblepresence of confounders, which could influence indi-vidual patient responses and hence the generalizability ofthese observations requires caution.

In 2002, our institution embarked on a program todecrease the use of fresh-frozen plasma (FFP) and weencountered concern on the part of the prescribing phy-sician regarding anaphylactoid reactions to IV vitamin K.This concern is appropriate, but needs to be placed incontext. Such reactions are considered to have been morecommon with older formulations of vitamin K in whichthe fat soluble vitamin was solubilized in polyethoxylatedcaster oil but available data indicate that such reactionsare less with current formulations, which use a polyoxy-ethylated fatty acid derivative. Nevertheless, the true inci-dence cannot be accurately estimated.27 An importantretrospective observational study showed two anaphylac-toid reactions in 6572 IV administrations, or a point esti-mate of 1:3290.33 However, the 95% confidence intervals(CIs) of this estimate are between 1:1000 and 1:250,000.Anaphylactic reactions to plasma also occur. Similarly, theincidence of such reactions to plasma cannot be accu-rately calculated from available reports. One report fromthe UK SHOT data34 showed 17 anaphylactic reactions in300,000 plasma units transfused, which gives a point esti-mate of 1:17,650 per unit. The 95% CIs of this estimate are1:3000 to 1:680,000. Since plasma is commonly dosed at20 mL/kg or 4 to 6 units in an adult, the risk of suchplasma transfusion could be between 1:500 and 1:100,000.From such estimates, it is reasonable to conclude thatanaphylactic reactions to both FFP and IV vitamin K arevery rare and that there is no statistical difference betweeneither approach. FFP (or prothrombin complex concen-trates) should be administered promptly for an immediateeffect35 where there is life- or limb-threatening bleeding,concurrently with IV vitamin K for a more sustained war-farin reversal. All IV administrations of vitamin K shouldbe as a slow infusion (>30 min) with careful monitoring forrare severe reactions.30,33

We recognize that there are previous reports examin-ing vitamin K use in this context but some new or impor-tant observations are presented. First, we have identified

Fig. 3. Bubble graph of the relationship between dose of vita-

min K given versus the median change in INR (DINR). The

diameter of the bubble is determined by the number of events

at any given dose.



considerable delay in response to test result availability forour inpatient population.This is of importance since a longtime lag from recognition of the INR test result to theadministration of vitamin K compounds the known delayin the in vivo response to vitamin K, regardless of whetherit is administered PO or IV. Hence there is an opportunityfor the laboratory to communicate out of target range INRs(>3.5) to the floor at the time of test result availability,alerting the physician or caregiver to the potential need forvitamin K administration and reducing delay. Although alllaboratories communicate critical values for the INR, this istypically in excess of an INR of 5 or 6 and most commonlyperformed to alert physicians taking care of outpatients onwarfarin. Second, there are no large randomized controlledtrials using vitamin K over a large range of doses (0.5 to10 mg) and hence variation in dosing practices continues.Our study is the largest observational study on the use ofvitamin K to reverse warfarin, which includes a large doserange and reinforces that very large doses of vitamin K(10 mg) appear to be unnecessary for short-term partialreversal. Finally, it allows us to predict to the practicingphysician with confidence that the IV route in doses of 1 to5 mg can achieve an INR of 2 as early as 6 hours and reliablywithin 15 hours in a majority of patients and an INR close to1.5 in 24 hours (Figs. 1 and 2). A target INR of approximately2.0 is chosen as it is sometimes used in consensus guide-lines36 and corresponds closely to the previously quotedprothrombin ratio of 1.537 when the prothrombin time wasperformed using reagents with a high international sensi-tivity index, usually greater than 2.0 (1.52 = 2.25). From ourdata (and others) we cannot discern any difference in effi-cacy of reversal between 1 and 5 mg doses by either route,but in the absence of a RCT our practice is to use between 2and 5 mg depending on the clinical context and the senseof urgency on the part of the physician. We continue toobserve confusion regarding dosage and route of adminis-tration and believe that our report provides for some clari-fication. Application of this information has allowed us toadvocate for plasma avoidance in many clinical situationsin which plasma was previously used with impact onoverall plasma usage.26

Newer oral anticoagulants are being introduced toreplace warfarin.38 The oral direct thrombin inhibitordabigatran was recently licensed for use in the UnitedStates as thromboprophylaxis in atrial fibrillation andan oral anti-Xa, rivoroxaban, for thromboprophylaxisin orthopedic surgery and atrial fibrillation. However,dabigatran has a high risk of dyspepsia, which may limitits use in some patients,39 and there is a cost differencebetween these drugs.40 Furthermore, oral anti-IIa andanti-Xa drugs do not have an antidote. For these reasons,warfarin will likely continue to be used in the near futureand, hence, reliable prediction of pharmacologic reversalis useful data for the practicing physician, emphasizingplasma avoidance where possible.

ACKNOWLEDGMENTS

The authors acknowledge the assistance of Mark Curtis R.Ph. for

his invaluable assistance in providing information on vitamin K

doses and the technologists in the Blood Bank of Roger Williams

Hospital for assistance in actively promoting the program to

reduce plasma usage.

CONFLICT OF INTEREST

None.

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MEEHAN ET AL.


clinical experience with oral versus intravenous vitamin k for warfarin reversal

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