ACCP recommends against the routine use of pharmacogenetic testing for guiding
21 Further research is needed to determine the place of
warfarin pharmacogenetic testing.
CASE 11-6, QUESTION 4: How should E.N. be assessed and evaluated at this clinic appointment?
At each clinic visit, E.N. should be assessed for signs and symptoms of bleeding,
and for signs and symptoms of clot progression and/or recurrence. The accuracy and
reliability of the INR test should be also considered. Additionally, E.N. should be
asked about missed or extra doses of warfarin, dietary changes (increases or
decreases in vitamin K, alcohol use), medication changes, recent illnesses (such as
nausea/vomiting/fever/chills/diarrhea), any recent falls, and any known upcoming
procedures. Regardless of the INR result, all factors that may influence E.N.’s
anticoagulation status should be evaluated carefully.
CASE 11-6, QUESTION 5: After a thorough assessment, it is determined that E.N. has adhered to his
INR. How should his warfarin dosage be adjusted?
When overanticoagulation or underanticoagulation is verified, an adjustment in
warfarin dosing may be necessary. Table 11-22 describes approaches to warfarin
dosing adjustments for maintenance therapy. Typically, dosing adjustments of 5% to
20% of the total daily dose (or the total weekly dose) are appropriate to reach the
118 Because warfarin does not follow linear kinetics, small
adjustments in dose can lead to large INR changes, and thus large dose adjustments
(i.e., greater than a 20% increase or decrease of the total weekly dose) are not
recommended. These maintenance dosing guidelines should only be applied to
patients who have reached a steady state dose and not in the initiation phase of
Because E.N. is currently taking 5 mg daily, an adjustment of 15% would increase
his dosage to approximately 5.5 mg/day. This dosing adjustment can be made by
having him take one 5-mg tablet and half of a 1-mg tablet each day (same daily
dosing) or by having him take 7.5 mg 2 days per week and 5 mg all other days of the
week (alternate-day dosing). Patient preference about breaking tablets in half, the
likelihood of confusion about different tablet sizes, and potential confusion on taking
different doses on different days of the week should be the primary considerations
when selecting a dosing method.
Warfarin Dose Adjustment Nomogram for Maintenance Therapy
INR (Goal 2–3) Suggested change in total “weekly” dose
<1.5 Give extra one-time daily dose and increase weekly dose by 10%–20%
1.5–1.9 Increase weekly dose by 5%–15% (may give extra one-time daily dose)
b Hold up to one daily dose and decrease weekly dose by 5%–20%a
b Hold up to two daily doses and decrease weekly dose by 10%–20%a
If transient cause identified, may need not to increase/decrease weekly dose.
CASE 11-6, QUESTION 6: E.N. agrees to increase his warfarin dosage to 5.5 mg/day. A new prescription
reassessed and his anticoagulation status, including physical assessment, be re-evaluated?
It will take several days for his INR to reach a new steady state because of the
long elimination half-lives of both warfarin and the vitamin K-dependent clotting
factors. His INR should be rechecked approximately 1 week after a dosing
adjustment has been made. Once a stable dose has been reached, patient assessment
and INR monitoring typically occurs every 4 to 6 weeks. However, if E.N. displays
any signs of medical instability or nonadherence, a follow-up schedule of every 1 to
2 weeks is indicated (Table 11-23). For carefully selected patients with well-
controlled INRs, recall frequencies out to 12 weeks can be recommended.
patients taking warfarin with previously stable therapeutic INRs who present with a
single out-of-range INR of ≤ 0.5 below or above therapeutic, continuing the current
dose and testing the INR within 1 to 2 weeks is suggested, rather than changing the
Management of Overanticoagulation
Management of overanticoagulation depends on the clinical presentation of the
patient. In the case of an elevated INR without bleeding complications, interruption
of warfarin therapy by holding one or two doses until the INR returns to the
therapeutic range is usually sufficient.
21 Minor bleeding complications accompanied
by an elevated INR can also be managed by withholding warfarin therapy for a short
period until bleeding resolves. In either case, the patient should be questioned to
determine a possible cause for overanticoagulation, including intake of extra doses of
warfarin, changes in diet or alcohol intake, changes in underlying medical conditions,
or the use of other medications. In some cases, no apparent explanation is identified.
Depending on the cause, a reduction in the maintenance dosing of warfarin may be
Frequency of International Normalized Ratio Monitoring and Patient
Assessment during Warfarin Therapy
Outpatient flexible initiation method Daily through day 4, then within 3–5 days
Outpatient average daily dosing method Within 3–5 days, then within 1 week
After hospital discharge Within 3–5 days
First month of therapy Every 1–4 days until therapeutic, then weekly
Medically stable inpatients Every 1–3 days
Medically unstable inpatients Daily
After hospital discharge If stable, within 3–5 days; If unstable, within 1–3 days
Routine follow-up in medically stable and reliable
Routine follow-up in medically unstable or unreliable
Dose held today for significant over-anticoagulation In 1–2 days
Dosage change today Within 1–2 weeks
Dosage change <2 weeks ago Within 2–4 weeks
The time required for INR to return to the therapeutic range after warfarin is
withheld depends on several patient characteristics. Advanced age, lower warfarin
maintenance dose requirements, and higher INR are associated with increased time
120 Other factors that can prolong the time for INR to return to the
therapeutic range include decompensated heart failure, active malignancy, and recent
use of medications known to potentiate warfarin.
Although previously recommended and commonly used, low-dose vitamin K in
patients with elevated INR 4.5 to 10 and not bleeding is not associated with a
reduction in major bleeding, and is no longer routinely recommended.
patients with INRs greater than 10 and not bleeding may benefit from small doses of
oral vitamin K 1 to 2.5 mg. The decision on whether to give vitamin K in
nonbleeding patients needs to consider the patient’s individual risk for bleeding and
21 An oral dose of 1 to 2.5 mg can correct overanticoagulation in 24 to 48
hours without causing prolonged resistance to warfarin therapy, a problem commonly
seen with larger (10 mg) doses of vitamin K. Intramuscular administration is
contraindicated due to the risk of hematoma formation, and SC administration of
vitamin K is not recommended because of variable absorption.
IV doses of 0.5 to 1 mg of vitamin K can correct overanticoagulation within 24
6 This approach is also useful for reversal of therapeutic anticoagulation before
invasive procedures and can be used to correct overanticoagulation in high-risk
cases. Intravenous vitamin K should be diluted in a minimum of 50 mL intravenous
fluid and administered with an infusion pump over a minimum of 20 minutes to
prevent flushing, hypotension, and cardiovascular collapse.
symptoms resemble anaphylaxis, the mechanism of this adverse response is unclear:
It is not known whether it is caused by phytonadione or by the vehicle in which
phytonadione is formulated. If this adverse reaction occurs, administration of
epinephrine may be indicated, as well as other standard measures to support blood
pressure and maintain the airway.
Fresh frozen plasma or factor concentrates to replace clotting factors will decrease
the INR for 4 to 6 hours and should be administered as needed with careful
21 Supplementation with high-dose IV vitamin K (10 mg)
may also be indicated. Administration of IV vitamin K will reverse the effects of
warfarin within 6 to 12 hours. However, if continued warfarin therapy is indicated
when bleeding resolves, anticoagulation with heparin may be necessary for as long
as 7 to 14 days until the effect of high-dose vitamin K is diminished and warfarin
Hematochezia may be an early sign of more serious bleeding, but in many cases
this condition is associated with minor bleeding episodes and identifiable causes
such as hemorrhoids. In a reliable patient, holding the warfarin until the INR returns
to a therapeutic level usually suffices, along with the addition of a bowel regimen to
prevent straining with bowel movements, topical cream to minimize swelling and
irritation, increased fluids, and/or increased fiber intake. Because V.G. appears to
have only minor bleeding from the stool, is hemodynamically stable, and has a stable
hemoglobin, withholding warfarin is appropriate. If the patient has never had a
colonoscopy, then evaluation for the appropriateness of this test may be warranted.
positive. What effects might warfarin have on the fetus? Are UFH or LMWHs safer alternatives in this
Warfarin and other coumarin anticoagulants cross the placental barrier and may
place the fetus at risk for hemorrhage and teratogenic effects.
pregnancies that involve exposure to coumarin result in abnormal liveborn infants,
and up to 30% in spontaneous abortion or stillbirth. Congenital abnormalities such as
stippled calcifications and nasal cartilage hypoplasia primarily occurred in infants
born to mothers receiving warfarin during the first trimester of pregnancy, with the
highest risk during weeks 6 to 12. Other abnormalities, involving the central nervous
system and eyes, are more likely to occur when the mother is taking warfarin later in
the pregnancy. In addition, because warfarin crosses the placenta, fatal bleeding
Women of childbearing age who require anticoagulation should be counseled
about options for contraception. Patients who become pregnant while receiving
warfarin should be informed of the risks of continued anticoagulation to the fetus, as
well as the risk to themselves of discontinuing anticoagulation.
Other options for pregnant women who require anticoagulation include UFH and
122 Because these agents do not cross the placenta, they are preferred over
warfarin for use in pregnancy. Many clinical trials have validated the safety and
efficacy of UFH and LMWHs in the prevention and treatment of DVT and PE during
pregnancy, with LMWH generally preferred to UFH for long-term management
122,123 When used at full doses for the treatment of VTE during
pregnancy, dosing must be adjusted throughout the pregnancy to account for the
expected increase in the body weight of the mother and the reported increase in
clearance of LMWH during pregnancy.
124,125 Selected current recommendations for
use of anticoagulants in pregnancy are outlined in Table 11-24.
After being informed of the risks associated with warfarin, M.P. decided to
continue her pregnancy and to begin anticoagulation with LMWH. Because pregnant
women were excluded from clinical trials with the DOACs due to their increased
risk for maternal and fetal bleeding, their use in pregnancy is not recommended at this
time. Warfarin therapy should be discontinued immediately and LMWH initiated
using SC treatment doses as previously described. Dosing adjustments may be
required throughout pregnancy based on changes in body weight and clearance,
possibly guided by anti-factor Xa monitoring. Potential adverse effects of LMWH
use, including hemorrhage, thrombocytopenia, and osteoporosis, should be monitored
For women desiring spinal anesthesia during delivery, treatment doses of LMWH
should be discontinued a minimum of 24 hours before induction of labor, cesarean
section, or placement of an epidural catheter, and restarted no sooner than 24 hours
postoperatively, and with adequate hemostasis in place.
should not be used in anticoagulated women (i.e., within 24 hours of the last
treatment dose of LMWH, or for patients receiving IV UFH that have prolonged
aPTTs). In patients not receiving epidural catheters, postpartum anticoagulation may
be started 12 to 24 hours after delivery as long as there are no bleeding concerns.
Consider IV UFH in women at high risk of bleeding, with LMWH reasonable for
most women. Restart warfarin when hemostasis has occurred, bridging with UFH or
LMWH until the INR is therapeutic. Warfarin, LMWH, and UFH do not accumulate
in breast milk and do not induce anticoagulant effect in the infant and may be used in
; therefore, M.P. can safely breastfeed. The DOACs are not
currently recommended during breastfeeding.
Selected Recommendations for Anticoagulation during Pregnancy
Clinical Situation Antepartum Options Postpartum
Low risk of recurrent VTE (single
episode of VTE associated with
Clinical vigilance Prophylactic or intermediate dose
Moderate/high risk of recurrent
pregnancy- or estrogen-related
VTE, or multiple prior unprovoked
VTE not receiving long-term AC)
Prophylactic or intermediate dose
LMWH over clinical vigilance or
Prophylactic or intermediate dose
On long-term VKA Adjusted-dose LMWH or 75% of a
Prophylactic or intermediate dose
Prophylactic or intermediate dose
All other thrombophilias who have +
Clinical vigilance Prophylactic or intermediate dose
protein C or S deficient, VKA (INR
mutation and no positive FH for
Clinical vigilance Prophylactic or intermediate dose
All other thrombophilias with no
Clinical vigilance Clinical vigilance
Long-term oral anticoagulants for
hour postdose peak anti-factor
the 13th week, with substitution
by VKA until close to delivery
Long-term warfarin to prior INR
goal with UFH/LMWH overlap until
INR above lower limit of therapeutic
(At extremes of body weight modification of dose may be required).
Intermediate-dose LMWH: dalteparin 5,000 units SC q12h, enoxaparin 40 mg SC q12h.
heparin; VKA: vitamin K antagonist; VTE, venous thromboembolism.
Source: Bates SM et al. 9th ed. ACCP guidelines. Chest. 2012;141(2)(Suppl):e691S–e736S.
ANTICOAGULATION BEFORE CARDIOVERSION
In atrial fibrillation, atrial activity and atrial enlargement cause stasis of blood
within the atria and the left atrial appendage, which can result in atrial thrombus
formation. Atrial thrombus formation increases the risk of systemic embolization;
clinical manifestations include arterial embolization of the extremities or
embolization of the splenic, renal, or abdominal arteries. However, the most
prevalent site of embolization is the cerebral arterial system, resulting in transient
ischemic attack or stroke with potentially devastating neurologic and functional
impairment. Atrial fibrillation carries a fivefold risk of ischemic stroke without
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