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A Survey of Oral Vitamin K Use by Anticoagulation Clinics
Edward N. Libby, MD;
David A. Garcia, MD
Arch Intern Med. 2002;162:1893-1896.
ABSTRACT
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Background Despite published reports of its safety and efficacy, oral vitamin K
(phytonadione) may not be widely used for patients with warfarin-associated
coagulopathy. We tested the hypothesis that recommendations for phytonadione
use from the American College of Chest Physicians (ACCP) Fifth Consensus Conference
on Antithrombotic Therapy are not routinely incorporated into the clinical
practice of many anticoagulation clinics.
Methods Surveys were mailed to 100 separate clinics in the southwestern region
of the United States that are members of the Anticoagulation Forum, an association
of anticoagulation clinic personnel and medical directors in the United States
and Canada. Respondents were presented with 4 scenarios involving asymptomatic
patients taking warfarin whose international normalized ratio is supratherapeutic.
In each scenario, the respondents were told the patient's international normalized
ratio and whether the patient was at "high" risk for bleeding.
Results Of 53 respondents, 13 (25%) indicated that their clinics never use oral
phytonadione. Eighteen (34%) indicated that their clinics use subcutaneous
phytonadione, despite the absence of a recommendation for this in the ACCP
guidelines published in 1998. For each scenario, we made a judgment as to
whether the respondent's management was consistent with guidelines found in
the ACCP Fifth Consensus Conference on Antithrombotic Therapy. Overall, only
17 respondents (32%) provided all 4 answers consistent with the ACCP recommendations.
Conclusion For patients with supratherapeutic international normalized ratio values,
our survey suggests that a substantial number of anticoagulation clinics underutilize
oral phytonadione.
INTRODUCTION
TWO TO 3 MILLION patients in the United States are receiving long-term
anticoagulant therapy with warfarin. Therapy with warfarin carries the benefit
of prevention of thrombosis and the risk of hemorrhage. Published reports
of annual bleeding risk have reported episodes of major bleeding to be as
low as 1.3% per year in large, international trials of warfarin use to prevent
stroke in atrial fibrillation.1 In many of
these trials, patient selection and use of anticoagulation clinics with strict
protocols and highly trained staff probably influenced the outcomes favorably.
Much higher rates of major bleeding in patients receiving anticoagulation
of 3% to 7% per year have been reported in studies that examined more "real
world" examples of clinical care.2-3
These data suggest that there are 26 000 to 210 000 major bleeding
episodes related to warfarin use per year in the United States.
The risk of hemorrhage is related to a number of factors, including
increases in the international normalized ratio (INR), age, history of bleeding,
renal insufficiency, and history of peptic ulcer disease. Bleeding risk increases
dramatically as the INR rises above 4 to 5. Even brief episodes of time with
elevated INRs pose a significant risk of bleeding for patients.3
Recent reports show that patients in typical outpatient practices are above
or below the therapeutic range 50% of the time.4-5
In addition, these studies have suggested that the amount of time spent within
the therapeutic INR range is directly related to therapeutic efficacy and
inversely related to the risk of hemorrhage. Therefore, strategies that allow
the practitioner to keep patients taking anticoagulants within or close to
their therapeutic range while minimizing the amount of time spent with an
elevated INR should decrease the incidence of major hemorrhage related to
warfarin use.
Vitamin K (phytonadione) has been recognized for decades as a treatment
for excessive anticoagulation. Recently, several studies have documented the
efficacy of oral phytonadione in returning elevated INRs to therapeutic or
near-therapeutic levels within 24 to 48 hours.6-9
Published experience also suggests that use of oral phytonadione does not
cause clinically significant overcorrection of the INR.6-9
The 1998 and 2001 American College of Chest Physicians (ACCP) Consensus
Conferences on Antithrombotic Therapy give identical recommendations on the
use of vitamin K to manage excessive anticoagulation (Table 1).10-11 The American
Heart Association, the American College of Cardiology, and the Anticoagulation
Forum all endorse these recommendations for management of excessive anticoagulation.
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Table 1. Summary of the 1998 and 2001 ACCP Recommendations for the
Management of Supratherapeutic INRs*
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Despite these widely available recommendations, there is great variation
among anticoagulation clinics in the management of excessive anticoagulation
in patients without significant bleeding. To test the hypothesis that many
anticoagulation clinics do not follow the ACCP guidelines with respect to
oral phytonadione use, we mailed a survey to 100 anticoagulation clinics in
the southwestern United States.
METHODS
IDENTIFICATION OF ANTICOAGULATION CLINICS FOR STUDY
We mailed surveys to all of the 100 clinics listed in the southwest
region (New Mexico, Arizona, Louisiana, Arkansas, Texas, and Oklahoma) of
the Anticoagulation Forum, an international organization of clinics providing
care and management services to patients taking oral anticoagulants. A letter
accompanied the survey asking that a senior member of the clinic team (nurse,
pharmacist, or physician) who was familiar with the policies of the clinic
answer the survey and return the form. We did not categorize the survey answers
by the type (nurse, pharmacist, or physician) of respondent. Participants
were offered a $10 payment for completing and returning the survey. Three
months after the initial mailing, a follow-up letter was sent to those clinics
that had not responded.
The institutional review board of the University of New Mexico Health
Sciences Center, Albuquerque, approved the research protocol for this observational
study. Informed consent was not obtained from the respondents.
SURVEY CONTENT AND STRUCTURE
First, respondents were asked if their clinic ever used oral and/or
subcutaneous phytonadione. Respondents were then presented with 4 clinical
scenarios (Table 2), each describing
an asymptomatic patient without active bleeding whose INR was supratherapeutic.
The case presentations also offered information about each patient's overall
risk for bleeding and thrombosis. Cases were constructed so that the recommendations
from the ACCP Fifth Consensus Conference regarding treatment of elevated INR
values were directly applicable.
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Table 2. Four Scenarios Presented in Survey to Anticoagulation Forum
Members*
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In Table 2, cases A and
B each describe an asymptomatic patient without risk factors for bleeding
whose INR is between 6 and 7. The ACCP states that for an INR greater than
5 but less than 9 in a patient with no significant bleeding, either of 2 management
strategies is appropriate: (1) hold warfarin and recheck INR in 24 to 48 hours
or (2) hold warfarin, administer low-dose oral phytonadione, and recheck INR
in 24 to 48 hours.
Case C describes an asymptomatic patient with an INR of 6.3. The scenario
states the patient had a recent gastrointestinal hemorrhage and is "at high
risk for bleeding." Case D describes an asymptomatic patient with an INR of
9.8. In patients with an INR greater than 5 but less than 9 with an increased
risk of bleeding, the ACCP recommends the use of phytonadione (1-2.5 mg, orally).
According to ACCP guidelines, patients with an INR greater than 9 and without
significant bleeding should have their warfarin held and be administered phytonadione
(3-5 mg, orally). In these 2 cases, an answer was considered consistent with
ACCP guidelines only if it included the administration of the appropriate
dose of oral phytonadione.
In each case, respondents were asked to select the management strategy
that most closely reflected their clinic's usual practice. Their choices included
(1) continue warfarin at a reduced dose and recheck INR in 24 to 48 hours;
(2) omit the next warfarin dose and recheck INR in 24 to 48 hours; (3) omit
the next warfarin dose and administer oral phytonadione; or (4) "other" (for
this choice, participants were asked to write in their response). In addition,
some of the scenarios included 2 possible doses of oral phytonadione; 1 "low"
(1-2.5 mg) and 1 "high" (3-5 mg).
OUTCOME DEFINITION
We defined all respondents' management choices as either consistent
or not consistent with the recommendations of the 1998 ACCP Consensus Conference
on Antithrombotic Therapy (at the time this survey was conducted, the 2001
ACCP Consensus Conference on Antithrombotic Therapy was not yet in print).
For the purposes of the study, we considered nonspecific write-in strategies
(eg, "call MD") to be consistent with ACCP recommendations.
STATISTICAL ANALYSIS
The 95% confidence interval was calculated for the proportion of respondents
having answers consistent with the 1998 ACCP recommendations.
RESULTS
Of the 100 surveys that were mailed, 14 were returned due to an incorrect
address. These surveys were not counted in the study. Thirty-three clinics
did not respond. Of the 86 clinics that received surveys, 53 (62%) responded.
Of 53 respondents, 13 (25%) indicated that their clinics never used oral phytonadione.
Nineteen (36%) indicated that their clinics use subcutaneous phytonadione.
Thirteen clinics indicated they use both oral and subcutaneous forms of phytonadione.
In case A, more than 90% of respondents chose a strategy consistent
with ACCP recommendations (Figure 1).
Eighty-one percent chose only to omit a dose of warfarin, 11% chose to omit
1 dose and give low-dose oral phytonadione, 1% chose to continue warfarin
at a lower dose, and 7% chose "other." Most write-in responses were not consistent
with ACCP guidelines because they specified that warfarin be resumed at the
same dose.
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Proportion of respondents who gave answers consistent with American
College of Chest Physicians (ACCP) recommendations for each case scenario.
Bars represent upper limit of 95% confidence interval. INR indicates international
normalized ratio.
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In case B, a similarly large majority chose a strategy consistent with
ACCP guidelines. Eighty-six percent chose only to omit a dose of warfarin,
11% chose to omit 1 dose and give low-dose oral phytonadione, 1% chose to
continue warfarin at a lower dose, while 1 respondent (2%) chose "other."
In case C, in which the patient is described as being "at high risk
for bleeding," only 55% of respondents elected to administer low-dose (1-2.5
mg) oral phytonadione. Twenty-five percent chose only to omit warfarin and
recheck the INR in 24 to 48 hours, while 4% chose to give 2.5 to 5.0 mg of
oral phytonadione. Sixteen percent chose "other." Of these, 4 responses (7%)
included the possibility of low-dose oral phytonadione administration. Several
of the 5 write-in responses deemed inconsistent with ACCP recommendations
included plans to increase dietary vitamin K intake.
In case D, describing an asymptomatic patient with an INR greater than
9, 40% chose the response consistent with ACCP recommendations (to administer
3-5 mg of oral phytonadione while withholding the next dose of warfarin).
Thirty-eight percent chose only to omit warfarin and recheck the INR in 24
to 48 hours, and 11% elected to give low-dose (1-2.5 mg) oral phytonadione.
Six respondents (11%) chose "other"; 4 (7%) of these write-in responses were
considered consistent with ACCP recommendations. One of the 2 write-in responses
that did not conform to ACCP recommendations specified subcutaneous phytonadione
for this scenario.
Overall, 17 respondents (32%) answered all 4 case scenarios in a manner
consistent with ACCP recommendations.
COMMENT
Oral phytonadione is well established to return elevated INRs (5-9)
to less than 5 in 24 to 48 hours in 95% to 96% of patients without causing
later difficulty in the reestablishment of anticoagulation.6-9
Although randomized controlled trials have been too small to show statistically
significant decreases in bleeding rates, the natural history of untreated
high INRs suggests that oral phytonadione is likely to be of benefit for many
of these patients.3 We performed a MEDLINE
search from 1964 through February 2001 using the keywords "phytonadione" and
"thrombosis" and found no reports of thromboembolism associated with low-dose
(1-5 mg) oral phytonadione.
The results of our survey suggest that many anticoagulation clinics
do not routinely follow the recommendations of the ACCP Consensus Conference
regarding the use of oral phytonadione for the management of asymptomatic
patients whose anticoagulation is supratherapeutic. Thirty-five percent of
clinics stated that they used subcutaneous phytonadione. This mode of therapy
has not been recommended by the ACCP since 1995.12
In addition, numerous studies have documented that the absorption rate and
responses of patients to subcutaneous phytonadione are erratic.13-14
Interestingly, in cases C and D (depicting the patients at highest risk for
bleeding) the percentage of respondents who deviated from ACCP guidelines
was the highest. This is puzzling because these patients could benefit most
from returning the INR to lower levels quickly. Earlier studies have confirmed
that the ACCP guidelines are not adhered to but found that at very high INRs
(10-20) patients were more likely to receive phytonadione.15
It is possible that the personnel managing these facilities are unaware
of the recommendations, but this seems unlikely since they were identified
as members of a leadership group for anticoagulation clinics. At the time
we conducted the survey, the ACCP Fifth Consensus Conference recommendations
had been in print for over 2 years. We speculate that many of the respondents
base their management decisions on historical practice rather than on the
recommendations of experts or evidence-based guidelines. Perhaps anecdotes
of thrombosis associated with high doses of parenteral phytonadione have made
some practitioners reluctant to follow recommendations that include the use
of oral phytonadione. Finally, we acknowledge that the ACCP Consensus Conference
recommendations on the management of nontherapeutic INRs are described by
their authors as "grade 2C" ("very weak recommendations, other alternatives
may be equally reasonable").
The ability to generalize our results is limited by the number of clinics
that failed to respond and by the fact that we mailed questionnaires to only
one region. Furthermore, responses to questions about fictitious patients
may not accurately reflect actual practice.
In conclusion, the results of our survey suggest that many anticoagulation
clinics underuse oral phytonadione and manage elevated INR values in a manner
that differs significantly from published guidelines. This is of great concern
because the incidence of serious and life-threatening bleeding associated
with elevated INRs is real and potentially avoidable.
AUTHOR INFORMATION
Accepted for publication January 17, 2002.
This study was supported by research grants from DuPont Pharmaceuticals,
Wilmington, Del, and the Department of Internal Medicine, University of New
Mexico.
This study was presented at the International Society Meeting for Thrombosis
and Hemostasis, Paris, France, July 10, 2001.
We are very grateful to David Schade, MD, for his critical review of
the manuscript and to Tanya Morga, RN, for her assistance with this project.
Corresponding author and reprints: Edward N. Libby, MD, University
of New Mexico Hospital, Department of Internal Medicine 5ACC, 2211 Lomas NE,
Albuquerque, NM 87131 (e-mail: elibby{at}salud.unm.edu).
From the General Internal Medicine Division, Department of Internal
Medicine, University of New Mexico Health Sciences Center, Albuquerque.
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