This study evaluated adherence to a warfarin reversal protocol using phytonadione at a community hospital over 11 months. 65% of phytonadione orders were non-adherent, most commonly using higher doses than recommended or incorrect routes of administration. Higher doses and IV routes often provided no additional benefit over oral or IM doses. While all dose/route combinations reduced INR, 10 mg IV lowered it the most on average. The data suggest protocol education for medical staff and evaluating uses other than elevated INR/bleeding is needed.

1. METHODOLOGY & RESULTS
Darowan Akajagbor, Pharm.D., Valery L. Chu, B.S., Pharm.D., CACP, Henry Cohen, M.S., Pharm.D., FCCM, BCPP, CGP
Kingsbrook Jewish Medical Center • Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University • Brooklyn, New York
Corresponding Author: Dakajagbor@kingsbrook.org
No financial disclosures apply to authors
INTRODUCTION
In response to a lack of uniformity and evidence-based use of phytonadione to reverse
warfarin, Kings brook Jewish Medical Center (KJMC) implemented an institutional protocol
on January 1st 2009 to treat warfarin-induced elevated INR and/or bleeding based on the
2008 American College of Chest Physicians (ACCP) antithrombotic guidelines.
OBJECTIVES
 To assess adherence to KJMC’s warfarin reversal protocol for the management of elevated
INR and/or bleeding
 To assess the efficacy and safety of treatment of phytonadione at different doses and
routes of administration
METHODOLOGY
 This is a retrospective review of all acute care inpatients who received phytonadione at
any dose and route from January to November 2009
 Patients included in the protocol group:
o Received a dose of phytonadione for INR elevation and/or bleeding
o INR elevation and/or bleed was secondary to warfarin intake
 Protocol patients were stratified into groups based on INR ≥ 4 with or without bleeding,
and INR ≤ 4 with bleeding
 Data collected include:
o INR before and after treatment with phytonadione
o Hemoglobin and hematocrit on admission and on day of treatment with phytonadione
o Administration of blood transfusions and/or fresh frozen plasma
o Reported adverse drug events related to the administration of phytonadione or
warfarin
 Electronic data sources were used to obtain all information. These systems include
medication administration records, laboratory records, adverse drug event reports,
Pharmacy Application, computerized physician order entry (CPOE), and emergency
department and ambulatory care health records.
REFERENCE
Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of vitamin K
antagonists: American College of Chest Physicians evidence-based clinical practice
guidelines (8th edition). Chest. 2008;133(6 Suppl):160S-198S.
RESULTS (cont)
DISCUSSION
Indication for Phytonadione
In an unexpected finding, only 50 percent of phytonadione orders were indicated for warfarin reversal secondary
to elevated INRs and/or bleed (protocol group). The most common indications for the rest included pre-operative
patients (e.g., surgical procedures, PEG tube placements) with non-elevated INR and a few cases of
hypoprothrombinemia. The current protocol does not address these uses.
Protocol Adherence
Non-adherence to institutional phytonadione protocol for warfarin reversal was high (65.8%). The most common
deviation from protocol was higher than recommended dosing, with the 10 mg dose used in nearly 60% of cases.
The 10 mg dose, which is recommended as an IV dose for bleeding cases, appears to be only indicated in 34% of
cases identified to have bleeding. The 5 mg dose was also often used where the 2.5 mg dose was recommended.
Inappropriate route of administration was another common deviation, notably use of IV phytonadione in non-
bleeding cases. The 10 mg PO and IM dose combinations were often administered but are not recommended by
the protocol.
Use of FFP
One third of patients who received FFP were not found to have bleeding. This may be because bleeding was not
documented in records evaluated or patients had very high bleed risk and FFP was given preemptively.
Efficacy Comparison
Multiple phytonadione dose/route combinations were used but all were noted to reduce INR after one dose. In the
four most common pairs, the greatest INR reduction was seen with the 10 mg dose IV combination (74%). The next
three pairs (10 mg PO, 5 mg PO, 10 mg IM) lowered INR similarly by ~ 50%.
The data suggest that the use of higher doses or injectable route are often not necessary (especially when
deviating from the protocol). The 10 mg PO dose combination was used almost twice as much as the 5 mg PO, but
the INR reduction is almost equivalent (50% and 55% respectively), hence little additional benefit is obtained from
doubling the PO dose from 5 mg to 1o mg. Although a small number of cases received the 2.5 mg PO dose
combination, data suggests that the 2.5 mg dose is not inferior to the 10 mg SQ dose (54 % and 31% reduction
respectively)
Limitations
 We did not assess for warfarin resistance that may occur secondary to over-correction with phytonadione.
 Although multiple sources were used to identify indication for phytonadione, chart review was not done and a
rationale for protocol deviations could have been missed.
 The retrospective nature of this review does not allow for the full clinical picture to be analyzed, so there may have
been justification for uses classified as non-adherent in this evaluation.
CONCLUSIONS
Based on the high frequency of non-adherence to the phytonadione use protocol, the need to in-service medical staff
is clear, but it will also be beneficial to discuss any concerns they may have with the efficacy of recommended doses
and routes. No evidence in the medical literature supports use of higher phytonadione doses and IV route when
bleeding is not present, and this evaluation’s review of dose and route efficacy corroborates the existing
recommendations.
In addition, use of phytonadione in non-bleeding and/or elevated INR cases needs addressing, especially when used to
reduce INR pre-operatively. Developing a separate phytonadione protocol may be indicated in these cases, possibly in
collaboration with the Surgery service.
EVALUATION OF THE USE OF PHYTONADIONE IN
WARFARIN REVERSAL AT A COMMUNITY HOSPITAL
Table 1. KJMC Phytonadione Protocol for Warfarin Reversal in Elevated INR and/or Bleeding
INR Range and
Bleeding Status
Management Recommendations
INR >target range but
<5
No significant
bleeding
↓ Warfarin dose OR Omit next dose
• Monitor INR more frequently
• Resume at lower dose when INR is in target range
• When INR is slightly above target range, dose reductions may not be necessary
INR >5 but <9
No significant
bleeding
Omit 1-2 doses of warfarin OR
Omit 1 dose + vitamin K
P.O. 2.5 mg (if risk for bleed)
• Monitor INR more frequently
• Resume at lower dose when INR is in target range
INR >9
No significant
bleeding
• Hold warfarin + vitamin K P.O. 2.5-5 mg
• Monitor INR more frequently
• Administer additional vitamin K P.O. if needed
• Resume at lower dose when INR is in target range
Serious bleeding at
any INR
• Hold warfarin + vitamin K 10 mg slow I.V. infusion over 30 minutes
• Supplement with fresh frozen plasma, prothrombin complex concentrate, or
recombinant Factor VIIa, depending on urgency
Life-threatening
bleeding
• Hold warfarin + prothrombin complex concentrate or recombinant Factor VIIa +
vitamin K 10 mg slow I.V. infusion over 30 minutes
• Repeat if necessary, depending on INR
Table 2. Protocol Group Age and Sex Distribution
Demographic Frequency
Male 55 (39.0%)
Female 86 (61.0%)
Mean Age in years (range): 75.3 (25 – 95)
Table 3. Protocol Adherence
Percent (n)
Adherence 34.8% (49)
Non-Adherence 65.2% (92)
Other Findings
Table 6. Mean INR Reduction By All Dose/Route Combinations
DOSE ROUTE ↓ IN INR TOTAL PER GRP (n)
2.5 IV 6.78 1
2.5 PO 3.33 5
2.5 SQ 5.7 1
5 IM 3.07 2
5 IV 5.27 4
5 PO 2.91 34
7.5 PO 2.29 1
10 IM 2.62 12
10 IV 5.1 46
10 PO 3.88 20
10 SQ 1.53 4
Figure 1.
Medication Use
Evaluation Flow
Diagram
65%
19%
16%
INR > 4
INR >4 + Bleed
INR < 4 + Bleed
Figure 2. Protocol Group Distribution
6.5
8.5
9.02
9.3
0 2 4 6 8 10
PO
IM
IV
SQ
PO IM IV SQ
Figure 6. Mean Doses for Different Routes of administration
Figure 8. Mean Reduction in INR from Day 0 to Day 1
Mean dose
Figure 9. INR Reduction By Most Common Dose/Route
Combinations
%INRreductionMeanINR
All phytonadione orders reviewed
(n = 526)
Doses not given or subsequent
doses given within 24-hours
(n = 229)
Non-Protocol Group
Phytonadione for non-protocol
indications
(n = 148)
Elevated INR ≥4 +
Bleeding
(n = 26)
INR ≤4 + Bleeding
(n = 22)
INR ≥4 without Bleeding
(n = 93)
Protocol Group
Phytonadione for elevated INR
and/or bleed
(n = 141)
Mean time from phytonadione dose to day 1 INR (16.7 hours)
Figure 5. Dose/Route Distribution
25% (36)
15% (21)
9% (13)
35% (49)
16% (22)
5 (PO)
10 (PO)
10 (IM)
10 (IV)
OTHERS
n = 141
OTHERS – 2.5 IV; 2.5 SQ; 2.5 PO; 5 IV; 5 IM; 7.5 PO; 10 SQ
Figure 4. Reasons for Protocol Non-adherence
62.0%
81.5%
1.0%
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0%
Incorrect route
Dose (too high)
Dose (too low)
Figure 3 . Protocol Group Service Distribution
63% (89)
16% (22)
11% (15)
11% (15)
Medicine
ED
Critical Care
Rehab
N = 141
31
50 50
54 55
74
0
10
20
30
40
50
60
70
80
10 mg 5 mg 10 mg 2.5 mg 10 mg 10 mg
SQ PO IM PO PO IV
Table 5. Frequency of Surrogate Markers for Bleeding % (n)
INR ≥4
No bleed
INR ≥4
Bleed
INR <4
Bleed
Blood Transfusion 9.9 (14) 3.5 (5) 7.8 (11)
Fresh frozen plasma 6.4 (9) 6.3 (9) 5.7 (8)
Hemoglobin ↓ by ≥4 g/dL 1.4 (2) 0 (0) <1 (1)
Hemoglobin ↓ to <7 g/dL 2.8 (4) <1 (1) 1.4 (2)
9.5
6.18
7.37
8.76
6.77
5.86 5.31 5.2
6.88 7.06
4.94
2.72 2.85
1.67
5.7
1.51
2.96
2.29 2.58
1.78
3.18 3.41
0
2
4
6
8
10
2.5 mg 2.5 mg 2.5 mg 5 mg 5 mg 5 mg 7.5 mg 10 mg 10 mg 10 mg 10 mg
IV PO SQ IM IV PO PO IM IV PO SQ
DAY 0 INR DAY 1 INR
Dose/Route Data
Adherence Data
Demographic Data