Cases & Commentaries

Crossed Coverage

Commentary By Steven R. Kayser, PharmD

The Case

A 27-year-old woman with a history of congenital
heart disease was admitted for cardiac transplantation evaluation.
She had already undergone multiple surgeries, including aortic
valve replacement for which she was on warfarin with a goal
international normalized ratio (INR) level of 2.0–3.0.

On admission, her hemoglobin level was normal and
her INR was 2.6. At the admitting hospital, a formal policy
required that all inpatient orders for warfarin be rewritten each
day to prevent overdosing. The intern caring for the patient
ordered her usual outpatient dose of 15 mg x 1. On hospital day
two, the patient's INR had risen to 3.6. The intern did not write
the order for warfarin for hospital day two and clearly outlined in
the daily progress note that the warfarin was to be held.

After the shift change, the evening nurse noted
that the daily warfarin order had not been written. She was
puzzled, as she distinctly remembered from signout that the patient
was on warfarin for the prosthetic aortic valve. Without checking
the progress notes or the laboratory values for that day, she paged
the night float intern (not the primary intern caring for the
patient) who was cross-covering. Having not received a verbal
signout from the primary intern, the cross-covering intern reviewed
the written signout on the patient and noted that warfarin was
listed as one of the patient's medications. As it turns out, the
primary intern had not updated the written signout that day, and
warfarin was still listed as an active medication. Without checking
the progress notes or the patient's INR level for the day, the
cross-covering intern gave the nurse a verbal order to give the
patient one dose of warfarin, 15 mg.

The pharmacy dispensed the medication, and the
patient received 15 mg of warfarin. The next day, the patient's INR
was 5.6; 3 days later, it peaked at 7.7. Oral vitamin K was given
to counteract the effects of the warfarin. The patient had a minor
nosebleed but no other adverse consequences.

The Commentary

Anticoagulant drugs are among the most common
agents responsible for adverse events in hospitalized patients as
well as a frequent cause of medication errors.(1) Warfarin, in particular, can be quite
dangerous—the narrow therapeutic index and its variable
pharmacologic response require careful dosing and management.

Efforts to improve the quality and safety of
warfarin administration include publishing standardized guidelines,
enforcing institutional dosing policies, and using computerized
physician order entry (CPOE) with clinical decision support.
Although distributing evidence-based guidelines for anticoagulant
medication administration resulted in a trend toward a decrease in
anticoagulant-associated adverse events in one study (2),
these interventions are generally unsuccessful, as they are only
advisory in nature and require no action on the part of the
provider. Proper and safe dosing requires the provider to refer to
the guidelines and subsequently use them appropriately. An example
of a warfarin dosing guideline is shown in the Table.

Many hospitals have implemented institutional
warfarin dosing policies that require the medication to be
prescribed and dispensed in a specifically described manner. One
example is a policy that eliminates standing orders for warfarin
and requires the order to be rewritten each day as a one-time
order. A similar policy was in place at the admitting hospital in
the case described, but it clearly did not prevent the error. For
high-risk drugs like warfarin, another policy that potentially
could reduce errors would mandate a specific order when the intent
is to discontinue or withhold a dose (as opposed to when the
intention is to give the medication). Such a policy could have
helped prevent the error in this case. Lastly, warfarin is
traditionally dosed in the evening. Requiring morning
administration could prevent errors since more staff members
(including the primary team responsible for a patient's care) are
in the hospital at this time and available to clarify orders.

Although not widespread, many hospitals have
implemented CPOE with clinical decision support to aid in the
dosing and management of warfarin. An alert triggered by the
association of warfarin with an INR that exceeds a certain value
(e.g., greater than 3.5) and supported by a management algorithm
might have prevented the error that occurred in this case. A system
designed to consider conflicting medications and comorbidities that
influence warfarin might be able to recommend specific doses.
However, with just computerized order entry, medication errors
persist. In one hospital where CPOE has been in place for a number
of years, anticoagulants accounted for 7.2% of all medication
errors, with warfarin accounting for 21.5% of these.(1) Of the anticoagulant-related adverse events, 6.2%
required medical attention and 1.5% resulted in prolonged hospital
stay. The most common errors were missed or extra doses.(1)

One alternative strategy to enhance the quality
and safety of inpatient anticoagulation administration is the
active engagement of inpatient pharmacists. For example,
pharmacy-managed inpatient anticoagulation consultation services
have been demonstrated to improve the use of anticoagulants,
including a reduction in the number of supratherapeutic INRs and a
decrease in bleeding incidents and the use of
transfusions.(3) In
most inpatient anticoagulation services, the pharmacist provides a
chart note with specific recommendations about dosing, which is
then reviewed by the physician who can either accept or reject the
recommendation. Although this kind of service can prevent many
errors, it may not have prevented the error in this case, since the
chart was not consulted and the pharmacist's note is only advisory
in nature.(4) On
the other hand, a program of direct anticoagulation management by
the pharmacist upon the request of a physician may have prevented
the error in this case. Most of these programs are voluntary, so
the availability of this service also might not have prevented the
error.(5)

The majority of preventable adverse drug events
occur at the time of either ordering or administration.(6) The
pharmacy is in an ideal position to prevent errors at both
junctions, since the nurse depends on pharmacy processing to be
able to access the medication and administer it. Policies could be
established that require the dispensing pharmacy to check the
laboratory data for each patient prior to processing an order. In
this case, such a policy would have led the pharmacist to observe
that the INR rose acutely (2.6 to 3.6) and to contact the physician
to intervene. A more comprehensive program would establish a
pharmacy-directed anticoagulation dosing service on a
24-hours-a-day, 7-days-a-week basis that includes all patients
receiving warfarin.(7)

Another potential solution is using electronic
laboratory alerts based upon certain rules, which are directed to a
dedicated anticoagulation pharmacist prior to the dispensing of the
medication.(8,9)
For example, when any two consecutive INR levels differed by more
than 0.4 units, an alert could be forwarded to the pharmacist for
review and potential intervention. The use of alerts during
medication ordering has met with variable success. In a setting of
patients residing in an academically affiliated long-term care
facility, alerts directed to physicians resulted in only a slight
increase in the likelihood of taking appropriate action (although
alerts related to warfarin were the most likely to result in an
action).(10) In
the case under discussion, an alert associated with a "rule" that
was linked to the laboratory result might have caught the warfarin
error. Our institution uses such a system, in which an electronic
laboratory alert is generated for certain anticoagulation-related
laboratory values and directed to a dedicated anticoagulation
pharmacist, and it works well.(11)

Overall, multiple failures of communication
occurred in this case. When the nurse noticed that no warfarin
order was written, as part of her scope of practice, she should
have reviewed the progress note to see if the omission was
intentional. The primary intern should have updated the written
signout or provided a better verbal signout to the cross-covering
intern. Enforcement of a no verbal order policy might have led the
cross-covering intern to look at the chart prior to writing the
order. The covering intern should have reviewed the laboratory
results prior to ordering the medication.

Although there were many human errors, a better
system probably would have prevented this error. Institutional
policies requiring an order when warfarin is to be discontinued or
held, or requiring that it be ordered only in the morning, may have
helped. A clinical decision support component of CPOE might have
prevented the error if it were designed to respond to either a
threshold INR or change in INR of a predetermined
magnitude.(12)
Finally, a dedicated, pharmacist-managed anticoagulation service
available 24 hours a day, 7 days a week, with or without computer
clinical decision support, is most likely to prevent these types of
adverse reactions. This type of service could also deal with other
anticoagulant-related issues that may arise.

Take-Home Points

  • When a medication, especially a
    high-risk one, is not ordered, the chart should be reviewed by
    physicians, nurses, and pharmacists to inquire if it was
    intentional.
  • A no verbal order policy should be
    strongly considered.
  • Mandatory review of laboratory data
    should be required with warfarin dosing.
  • Pharmacy-directed anticoagulation
    services should be considered.

Steven R. Kayser, PharmD
Professor of Clinical Pharmacy
School of Pharmacy
University of California, San Francisco

References

1. Fanikos H, Stapinski C, Koo S, et al.
Medication errors associated with anticoagulant therapy in the
hospital. Am J Cardiol. 2004;94:532-535.
[go to PubMed]

2. Schumock GT, Blackburn JC, Nutescu EA, et al.
Impact of prescribing guidelines for inpatient anticoagulation. Ann
Pharmacother. 2004;38:1570-1575.
[go to PubMed]

3. Bond CA, Raehl CL. Pharmacist-provided
anticoagulation management in United States hospitals: death rates,
length of stay, Medicare charges, bleeding complications, and
transfusions. Pharmacotherapy. 2004;24:953-963.
[go to PubMed]

4. Dager WE, Branch JM, King JH, et al.
Optimization of inpatient warfarin therapy: impact of daily
consultation by a pharmacist-managed anticoagulation service. Ann
Pharmacother. 2000;34:567-572.
[go to PubMed]

5. Mamdami MM, Racine E, McCreadie S, et al.
Clinical and economic effectiveness of an inpatient anticoagulation
service. Pharmacotherapy. 1999;19:1064-1074.
[go to PubMed]

6. Bates DW, Cullen DJ, Laird N, et al. Incidence
of adverse drug events and potential adverse drug events.
Implications for prevention. ADE Prevention Study Group. JAMA.
1995;274:29-34.
[go to PubMed]

7. Burns N. Evaluation of warfarin dosing by
pharmacists for elderly medical in-patients. Pharm World Sci.
2004;26:232-237.
[go to PubMed]

8. Hartis CE, Gum MO, Lederer JW Jr. Use of
specific indicators to detect warfarin-related adverse events. Am J
Health Syst Pharm. 2005;62:1683-1688.
[go to PubMed]

9. Lederer J, Best D. Reduction in
anticoagulation-related adverse drug events using a trigger-based
methodology. Jt Comm J Qual Patient Saf. 2005;31:313-318.

[go to PubMed]

10. Judge J, Field TS, DeFlorio M, et al.
Prescribers' responses to alerts during medication ordering in the
long term care setting. J Am Med Inform Assoc. 2006;13:385-390.

[go to PubMed]

11. Comprehensive Hemostasis and Antithrombotic
Service (CHAS), UCSF Medical Center.

12. Nebeker JR, Hoffman JM, Weir CR, Bennett CL,
Hurdle JF. High rates of adverse drug events in a highly
computerized hospital. Arch Intern Med. 2005;165:1111-1116.

[go to PubMed]

Table

Guidelines for Warfarin Dosing

Warfarin orders must be written daily (i.e., no standing
orders).
INR must be monitored daily.
An INR increase of 0.2–0.3 units per day represents an
optimal response to initiation of warfarin. Any increase in INR
greater than or equal to 0.4 units per day should result in
warfarin dose reduction or holding warfarin dose.
INRs should not be assessed when activated partial
thromboplastin time (aPTT) is >100 seconds, due to the
contribution of unfractionated heparin's effect to INR. Wait until
aPTT is
For INRs significantly above the therapeutic range, hold
warfarin until INR falls within range prior to restarting
warfarin.
Factors that may impact the INR: drug interactions,
malnutrition, alcohol, concomitant disease (e.g., thyroid
dysfunction, liver disease, fever), medication adherence.
Algorithm for Initiating Warfarin in
Hospitalized Patients [Baseline prothrombin time (PT)/INR,
partial thromboplastin time (PTT), and platelet count must be
obtained prior to initiation of warfarin.]
Day INR Action
1   5 mg (2.5 or 7.5 mg in select populations)
2 Less than 1.5 Continue dose
Greater than or equal to 1.5 Decrease or hold dose*
3 Less than or equal to 1.2 Increase dose*
Greater than 1.2 and less than 1.7 Continue dose
Greater than or equal to 1.7 Decrease dose*
4 (or until therapeutic) Daily increase is less than 0.2 units Increase dose*
Daily increase is 0.2–0.3 units Continue dose
Daily increase is 0.4–0.6 units Decrease dose*
Daily increase is greater than or equal to 0.7 units Hold dose

*In general, dosage adjustments should not exceed 2.5 mg or
50%.

Factors to Consider When Initiating Warfarin
Usual initiation dose = 5 mg (NOT 10 mg)
Consider higher initial dose (e.g., 7.5 mg) in the following
populations:
    1. Weight >85 kg
    2. African-American patients
    3. Clinical hypothyroidism
    4. Concomitant medications
Consider lower initial dose (e.g., 2.5 mg) in the following
populations:
    1. Frail or advanced age (older than
75)
    2. Asian patients
    3. Hepatic insufficiency
    4. Malnutrition/poor PO intake
    5. Clinical hyperthyroidism
    6. High bleeding risk
    7. Concomitant medications