Cases & Commentaries

Bleeding Risk

Commentary By Mark A. Crowther, MD, MSc

The Case

A frail 78-year-old woman fell at home and
fractured her left hip. Her past medical history included atrial
fibrillation, hypertension, coronary artery disease, and stroke.
The surgical repair and post-operative course were uneventful. The
patient was discharged to a skilled nursing facility (SNF) for
physical therapy on low-molecular-weight heparin, with a plan to
initiate warfarin once it became clear that that she was not at
high risk for falls.

Two weeks into her admission at the SNF, the
patient’s physician began warfarin therapy at 5 mg daily. An
INR level taken 3 days later was 1.5. Heparin was discontinued and
warfarin was increased to 6 mg daily. An INR level was not ordered
to be drawn for 7 days, at which time it was at a critical level of
20 (therapeutic range 2-3). The physician discontinued warfarin,
but no other therapy was administered to reverse the anticoagulant
effect. A repeat INR 3 days later was 12. A one time order for 10
mg of Vitamin K intramuscularly (IM) was administered. A repeat INR
was ordered 2 days later, at which time it was 4.4—elevated
but no longer critical. Two days after that, the INR was
subtherapeutic at 1.4. At that point, the physician reinitiated
warfarin at the original dosage of 5 mg daily. The INR did not
become therapeutic for another 12 days, presumably because of the
Vitamin K effect.

The Commentary

Warfarin is a highly effective, widely
implemented, and well-proven intervention that markedly reduces the
risk of both first and recurrent arterial and venous thrombosis.
However, warfarin has a narrow therapeutic window and highly
variable pharmacokinetics, both between individuals and within an
individual over time. The fact that warfarin has variable
pharmacokinetics has led to the development of a widespread
infrastructure for its monitoring. Unlike other medications, the
anticoagulant effect of warfarin can be routinely and reliably
determined within hours in most hospital and outpatient
laboratories.

The principal complication of warfarin therapy is
hemorrhage. Although hemorrhage can occur in any patient receiving
warfarin, the risk is magnified when the anticoagulant effect
exceeds the usual therapeutic interval. Increasing the
international normalized ratio (INR) by one point approximately
doubles the risk of bleeding.(1) Unexpected
excessive prolongation of the INR is a common clinical problem;
about 1 in 6 INR values will exceed the desired range. The risk of
major bleeding is about 5% in the 2 weeks after patients present
with an INR of more than 6.0 if they are treated with warfarin
withdrawal alone.(1-3)

Monitoring the INR by experienced professionals
reduces the risk of excessive (or inadequate) anticoagulation with
the associated risks of bleeding (or thrombosis).(4) Thus,
numerous studies have suggested that monitoring of oral
anticoagulants in dedicated thrombosis clinics, using intelligent
computer programs or patient self-monitoring with point-of-care INR
testing, increases the time in the therapeutic range and reduces
out-of-range INR values, the need for blood tests, and the costs
and inconvenience of warfarin therapy.(4,5) In
the hospital setting, where supervision of warfarin therapy is
likely to be required regularly, development of a warfarin dosing
algorithm for initial therapy and the use of either experienced
staff or a computerized dosing system will likely reduce the risk
of out-of-range INR values with their associated complications.
These systems are also likely to detect changes in the
patient’s clinical condition or medication regimen that might
increase the risk of out-of-range INR values (Table).

Medication errors specific to oral anticoagulants
generally occur either due to inadequate monitoring,
co-administration of medications that interact with warfarin, or
inadequate treatment of excessively prolonged INR values. However,
despite the number of patients who receive warfarin, and the
frequency of excessively prolonged INR values, there has been
little research into the frequency, clinical implications and costs
of inappropriate warfarin dosing. However, several studies have
recently been published which help to guide the management of
patients with warfarin-associated coagulopathy.

A number of warfarin dosing algorithms have been
developed.(6,7) These
algorithms guide the frequency of INR determinations and the
warfarin dose recommended based on the INR. For inpatients, INR
determinations can be performed daily in the first days of warfarin
therapy. For outpatients, less frequent monitoring can be
performed; however, monitoring should occur at least biweekly
during the early phase of therapy. Once a stable dosage of warfarin
is achieved, the frequency of INR monitoring can be reduced to
weekly for a period of 2 to 3 weeks, then monthly. If medications
or diet are changed, increased monitoring of the INR is
required.(8)

When patients present with an increased INR, the
first priority is to determine if they are bleeding. Patients with
major or life-threatening bleeding should receive parenteral
vitamin K and coagulation factors; treatment of such patients is
beyond the scope of this review, but has been reviewed in detail
elsewhere.(9) For
non-bleeding patients, two options are available: simple withdrawal
of warfarin or administration of low-dose oral vitamin K.(10,11) Although
the former strategy remains the standard of practice, it is likely
associated with potentially avoidable major hemorrhage or
death.(1) Therefore,
the use of low-dose oral vitamin K is generally best in these
situations. Administration of 1 mg of oral vitamin K reliably
reduces INR values of 4.5 to 10.0 into the therapeutic range within
24 hours.(10) Although
not studied, use of somewhat higher doses (eg, 2 mg to 2.5 mg
orally) is likely effective in patients with higher INR values.
Small doses of vitamin K have not been reported to produce
“warfarin resistance” or to cause prolonged
subtherapeutic INR values (both concerns have been raised in the
past as reasons to avoid oral vitamin K). Subcutaneous vitamin K is
less effective than oral, and its use cannot be recommended except
in patients who cannot take oral medications.(12)
Alternately, 0.5 mg of vitamin K intravenously reliably reduces
markedly prolonged INR values into the therapeutic range within 24
hours.(13) The risk of
anaphylaxis with intravenous vitamin K has never been quantified,
but appears to be very low. In all patients, the INR should be
rechecked on the following day to ensure that it has fallen, which
did not occur in this case.

This case illustrates a number of important
issues. Warfarin is indicated in this case because of the atrial
fibrillation; it also reduces the risk of DVT after orthopedic
surgery when used after hospital discharge. The initial warfarin
dosage was appropriate; however, it is worth keeping in mind that
post-operative patients often require smaller dosages of warfarin
than patients who have not had recent surgery.(14)
Thus using a smaller initial dosage of warfarin (eg, 3 mg) would
have likely also been effective. The initial INR on day 3 is also
appropriate. It is likely that continuing the warfarin at 5 mg per
day would have resulted in a therapeutic INR. Although increasing
the dosage is not unreasonable, the INR should have been monitored
within 72 hours of the change. Some nursing facilities have routine
bloodwork scheduled only weekly. For patients initiating warfarin,
bloodwork will be required more often, and thus alternate
arrangements are required.

When the INR is 20, most physicians would be
uncomfortable simply withholding warfarin; administration of
vitamin K is probably indicated in this circumstance.(4) However, the
dose of vitamin K (10 mg) was excessive in this case, and the route
(intramuscular) was both unneeded (oral vitamin K being effective)
and potentially dangerous (given the coagulopathy). The poor
response of the INR to this large dose of vitamin K illustrates the
relative ineffectiveness of vitamin K given by this route. If it
had been given orally, the INR would likely have reached the
desired range within 24 to 48 hours. It is also likely that if the
dosage of warfarin had originally been left at 5 mg, and the INR
monitored more closely, this entire scenario could have been
avoided.

Take-Home Points

  • Oral warfarin is safe and effective in
    the treatment and prevention of many thromboembolic disorders, but
    it has a relatively narrow therapeutic window.
  • The use of published standard dosing
    algorithms may increase the safety of initial warfarin dosing.
  • In the early days of therapy, fail-safe
    plans should be in place for frequent INR monitoring. This
    frequency can be cut back once a stable INR is achieved.
  • Warfarin over-dosage places patients at
    risk for bleeding, particularly when the INR is above 6.0.
  • Patients with supra-therapeutic INRs and
    active hemorrhage should receive parenteral vitamin K and clotting
    factors. For patients with supra-therapeutic INRs who are not
    bleeding, low-dose oral vitamin K is generally more effective than
    simply holding the warfarin in promptly reducing the INR.

Mark
A. Crowther, MD, MSc
Associate Professor of Medicine
McMaster University
Hamilton, Ontario, Canada

References

1. Hylek EM, Chang YC, Skates SJ, Hughes RA,
Singer DE. Prospective study of the outcomes of ambulatory patients
with excessive warfarin anticoagulation. Arch Intern Med.
2000;160:1612-1617.[ go to PubMed ]

2. Kearon C, Gent M, Hirsh J, et al. A comparison
of three months of anticoagulation with extended anticoagulation
for a first episode of idiopathic venous thromboembolism. N Engl J
Med. 1999; 340:901-907.[ go to PubMed ]

3. Oden A, Fahlen M. Oral anticoagulation and
risk of death: a medical record linkage study. BMJ.
2002;325:1073-1075.[ go to PubMed ]

4. Ansell J, Hirsh J, Dalen J, et al. Managing
Oral Anticoagulant Therapy. Chest. 2001;119:22S-38S.[ go to PubMed ]

5. Poller L, Shiach CR, MacCallum PK, et al.
Multicentre randomised study of computerised anticoagulant dosage.
European concerted action on Anticoagulation. Lancet.
1998;352:1505-1509.[ go to PubMed ]

6. Kovacs M, Cruickshank M, Wells PS, Kim H,
Chin-Yee I, Morrow B et al. Randomized assessment of a warfarin
nomogram for initial oral anticoagulation after venous
thromboembolic disease. Haemostasis. 1998;28:62-68.[ go to PubMed ]

7. Harrison L, Johnston M, Massicotte MP,
Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading
doses in initiation of warfarin therapy. Ann Intern Med.
1997;126:133-136.[ go to PubMed ]

8. Wells PS, Holbrook AM, Crowther NR, Hirsh J.
Interactions of warfarin with drugs and food. Ann Intern Med.
1994;121:676-683.[ go to PubMed ]

9. Warkentin TE, Crowther MA. Reversing
anticoagulants both old and new. Can J Anaesth.
2002;49:s11-s25.[ go to PubMed ]

10. Crowther MA, Julian J, Douketis JD, et al.
Treatment of warfarin-associated coagulopathy with oral vitamin K:
a randomized clinical trial. Lancet. 2000;356:1551-1553.[ go to PubMed ]

11. Glover JJ, Morrill GB. Conservative treatment
of overanticoagulated patients. Chest. 1995;108:987-990.[ go to PubMed ]

12. Crowther MA, Douketis JD, Schnurr T, et al.
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;137:251-254.[ go to PubMed ]

13. Shetty HG, Backhouse G, Bentley DP, Routledge
PA. Effective reversal of warfarin-induced excessive
anticoagulation with low dose vitamin K1. Thromb Haemost.
1992;67:13-15.[ go to PubMed ]

14. Ageno W, Turpie AG. Exaggerated initial
response to warfarin following heart valve replacement. Am J
Cardiol. 1999;84:905-908.[ go to PubMed ]

Table

Table. Causes of Abrupt Change in INR*

Causes of Increased INR

Examples

Reduced vitamin K availability

Use of antibiotics; unusual diets

Drug interactions

Drugs that inhibit metabolism of warfarin
(eg, sulfonamides, metronidazole, isoniazid, amiodarone)

Toxins

Alcohol use

Overdosage

Inappropriate pill strength dispensed;
intentional overdosage

Causes of Decreased INR

Examples

Enhanced vitamin K intake

Increased green leafy vegetables in
diet

Drug interactions

Drugs that enhance clearance of warfarin
or interfere with absorption (eg, rifampin, nafcillin,
sucralfate)

Underdosage

Poor compliance

* These lists are not intended to be
comprehensive; rather they should be used as a guide to the
investigation of patients with unexpected changes in their warfarin
requirements.