Current guidelines for bridging are based on the results of case series,
observational studies, and nonrandomized trials involving patients with various
indications for anticoagulation, including valve replacement. The decision to use
bridging depends on the risk of bleeding associated with continued anticoagulation
for the surgery or procedure to be performed and on the risk of thromboembolism
associated with underanticoagulation in the patient in question. Recently, a large
registry called The Outcomes Registry for Better Informed Treatment of Atrial
Fibrillation (ORBIT-AF) included patients with atrial fibrillation that underwent
temporary interruption of oral anticoagulation therapy and showed that bridging was
associated with higher risk of bleeding and adverse events.
interim results of the BRIDGE trial (Bridging Anticoagulation in Patients who
Require Temporary Interruption of Warfarin Therapy for an Elective Invasive
Procedure or Surgery) that randomized patients with atrial fibrillation to receive
bridging therapy with LMWH or placebo showed similar findings to the ORBIT-AF
registry. The study showed no difference in the rate of arterial thromboembolism
between the bridging and nonbridging group; however, the bridging group showed
significantly higher rates of major bleeding. The mean CHADS2 score was 2.3 and
patients with mechanical heart valve or stroke, systemic embolism, and transient
ischemic attack within the previous 12 weeks were excluded from the trial. Major
surgical procedures associated with high rates of arterial thromboembolism and
bleeding were also underrepresented. Therefore, the results from the BRIDGE trial
should not be applied to patients that were underrepresented.
Individualized risk assessment and bridge therapy planning are necessary for each
patient who may require temporary discontinuation of warfarin. Current
recommendations for risk stratification are outlined in Table 11-25. High-risk and
moderate-risk patients typically receive bridge therapy if warfarin needs to be
withheld, whereas in low-risk patients, warfarin is simply withheld before the
invasive procedure, without the need for bridging. The bleeding risk of a performed
procedure or surgery must also be weighed. Efforts should be made to continue oral
anticoagulation in a patient with high thromboembolic risk undergoing a procedure
with low-bleeding risk, such as a dental extraction or cataract surgery. Table 11-26
includes examples of high- versus low-bleeding risk surgeries.
Clinical outcomes in patients bridged with LMWH or UFH are similar and overall
costs are lower for LMWH because of the avoidance of hospital admission for IV
UFH administration; therefore, the use of LMWH is recommended whenever
145 UFH may be preferred in patients with significant renal impairment
(CrCl < 30 mL/minute), and if LMWHs are used, reduced doses are suggested.
Monitoring anti-Xa levels for accumulation may be prudent if patients require a
prolonged course of therapy (over 7 days). A guideline for bridge therapy based on
the risk of thromboembolism and on renal function is presented in Table 11-27.
Risk Stratification for Determining the Need for Bridge Therapy
Risk Stratum Mechanical Heart Valve Atrial Fibrillation Venous Thromboembolism
High Any mitral valve prosthesis
Moderate Bileaflet aortic valve
following: atrial fibrillation,
score of 3 or 4 VTE within the past 3 to 12
Bleed Risk of Selected Procedures
(2-Day Major Bleed Risk of 0%–2%)
(2-Day Major Bleed Risk of 2%–4%)
Abdominal hernia repair Abdominal aortic aneurysm repair
Cataract surgery Any surgery lasting > 45 minutes
Cholecystectomy Major cancer surgery
Colonoscopy Major cardiac surgery (heart valve replacement &
Cutaneous biopsies Major orthopedic surgery (joint replacement)
Cystoscopy Major vascular surgery
Dilation and curettage Transurethral prostate resection
Dental extractions Neurosurgical procedures
GI endoscopy ± biopsy Polypectomy, variceal treatment
Skin cancer excision Renal biopsy
Because L.P. has a mechanical mitral valve replacement, her risk of
thromboembolism associated with underanticoagulation is considered high.
Therefore, she should receive bridge therapy with an injectable anticoagulant while
warfarin is held. Her renal function is normal, and her healthcare insurance covers
injectable drugs. Therefore, her plan will include early discontinuation of warfarin 5
days before the procedure and substitution with enoxaparin 1 mg/kg every 12 hours
when the INR falls below the lower limit of the therapeutic range. The last dose of
enoxaparin should be given 24 hours before the procedure to minimize the risk of
bleeding at the time of the procedure. After the procedure, warfarin should be
restarted at her usual dose, and enoxaparin should be continued until the INR is
greater than 2.5, the lower limit of L.P.’s therapeutic range. For indications other than
mechanical valves, enoxaparin 1.5 mg/kg every 24 hours may be used as an
alternative to avoid twice-daily injections.
Interactions with Prescription Drugs
been anticoagulated with warfarin 6 mg/day with good control. She asks to see you today in your
(MRSA), and was given a prescription for trimethoprim–sulfamethoxazole (TMP-SMX) twice a day for 10
another drug substituted for TMP-SMX?
Bridge Therapy Guidelines of Invasive Procedures
Day Warfarin LMWH Laboratories
−6 Last warfarin dose N/A INR; skip dose if
−2 to −1 No warfarin LMWH; last dose 24–36
0—day of procedure Resume warfarin at usual
No LMWH Ensure INR is appropriate
2–3 Warfarin LMWH; resume following
5–7 Warfarin LMWH INR; discontinue when
Consider CBC, CrCl, antiXa level with continued
aConsider giving 1.5 times usual warfarin dose for first 2 days when warfarin reinitiated.
INR < 1.5 required for most surgical procedures.
Drug interactions with warfarin occur by a number of different mechanisms and
can have a significant impact on the anticoagulant effect of warfarin.
or reductions in INR have been observed when interacting drugs are added to or
discontinued from the medication regimens of patients taking warfarin or when used
intermittently. Clinically significant hemorrhagic or thromboembolic complications
can result. Careful selection of both prescription and nonprescription medications,
appropriate INR monitoring, and detailed patient education regarding drug
interactions are important interventions for pharmacists caring for patients taking
warfarin. A selection of the hundreds of drugs that have been reported to interact
with warfarin, including mechanisms of interaction and effect on INR, is provided in
Table 11-28. Further information regarding the management of drug interactions can
be found in Chapter 3, Drug Interactions.
Target Effect Response Examples (Not Inclusive)
Warfarin Inhibition Increased Acetaminophen Allopurinol Amiodarone Azole
Cimetidine Fluoroquinolones Macrolides Metronidazole
Propafenone SSRIs Statins Sulfa
Barbiturates Carbamazepine Doxycycline Griseofulvin
Nafcillin Phenytoin Primidone Rifampin
Aspirin NSAIDs Salicylates GPIIb/IIIa
Cholestyramine Colestipol Sucralfate
Ascorbic acid Azathioprine Corticosteroids Cyclosporine
Androgens Fenofibrate Cyclophosphamide Gemfibrozil
GP, glycoprotein; INR, international normalized ratio; LMWH, low-molecular-weight heparin; NSAIDs,
nonsteroidal anti-inflammatory drugs.
Although warfarin is highly bound to protein (primarily to albumin), and can be
displaced from protein-binding sites by a number of weakly acidic drugs, these
interactions typically do not result in clinically significant elevations in PT/INR.
Warfarin displaced from protein-binding sites is readily available for elimination by
hepatic metabolism, resulting in increased clearance without a significant change in
Other types of interactions with warfarin are much more significant.
Pharmacodynamic interactions are those that alter the physiology of hemostasis,
particularly interactions that influence the synthesis or degradation of clotting factors
or that increase the risk of bleeding through inhibition of platelet aggregation.
Pharmacokinetic interactions influence the absorption and metabolism of warfarin,
and many clinically significant interactions with warfarin occur when warfarin
metabolism is induced or inhibited. Interactions involving agents known to influence
the hepatic microsomal enzyme systems responsible for the metabolism of the more
potent S(−)-warfarin (CYP2C9) are more significant than those that influence the
enzymes that metabolize R(+)-warfarin (CYP1A2, CYP3A4).
Sulfamethoxazole can increase the effect of warfarin significantly by
stereoselectively inhibiting the metabolism of the more potent S(−)-enantiomer of
warfarin. Potentiation of warfarin activity after inhibition of metabolism usually
takes several days, and the effect may be slow to resolve once the offending agent is
discontinued. In addition, fever associated with the infection for which TMP-SMX
has been prescribed may enhance the catabolism of vitamin K-dependent clotting
factors, resulting in an accentuated hypoprothrombinemic response. This effect will
dissipate as the fever abates with antibiotic therapy.
For P.T., the ideal choice would be to discontinue TMP-SMX and use a
noninteracting alternative. The decision of which agent to use must consider both the
treatment(s) of choice for the clinical indication along with patient factors such as
reported allergies or intolerances. In P.T.’s case, she has a penicillin allergy and
intolerance to tetracyclines, both of which would prevent their use. If a noninteracting
alternative is not clinically appropriate, the concomitant use of an interacting agent is
not absolutely contraindicated in patients taking warfarin. Use of TMP-SMX in P.T.
would be acceptable if she is monitored frequently and carefully, with adjustment of
warfarin dosages as necessary to maintain her INR within the therapeutic INR range
of 2.5 to 3.5 and with attention to potential hemorrhagic complications. No initial
change in the dosage of warfarin should be made because it may take several days for
the interaction to become apparent. The INR should be repeated within 3 days, with
warfarin dosing adjustments and subsequent monitoring guided by initial INR results.
Although the DOACs are less prone to drug interactions than warfarin, all of them
are P-glycoprotein substrates and can have their concentrations reduced by rifampin,
which is a strong P-gp inducer.
151 At this time, dabigatran, rivaroxaban, apixaban,
and edoxaban are all contraindicated with rifampin per package labeling and are not
The interaction with warfarin and rifampin can be significant, with a potentially
large dose increase (sometimes up to 3 times the original dose) of warfarin necessary
to maintain G.H. in the therapeutic range. If G.H. is in a facility where his INRs can
be measured frequently, such as every few days, it may be appropriate to maintain
him on warfarin while continuing the rifampin, until the degree of the interaction can
be detected, and a new stable dose can be determined. Alternatively, if G.H. is
receiving the antibiotics at home, it may be appropriate for him to acquire a home
INR meter and perform warfarin self-testing of his INRs. It has been shown that
individuals performing patient self-testing (almost all testing weekly) had better time
in therapeutic range (TTR) than those who underwent in-clinic testing every 4 weeks
using high-quality anticoagulation management.
152 A substudy of this trial also
showed that individuals on chronic anticoagulation who perform self-testing more
often (i.e., weekly or twice weekly) had a modestly higher TTR compared to monthly
153 The costs of the self-testing meter and supplies are often covered by the
patient’s insurance; however, sometimes the poor reimbursement for managing
then patient self-testing can be a way to empower patients to take more control of
their warfarin management and reduce the burden of INR monitoring.
LMWH, UFH, and fondaparinux are also reasonable options for G.H. to use,
especially if his INRs cannot be stabilized while receiving the rifampin. However,
again, there could be barriers to self-injection and insurance limitations that may
make it difficult to continue these agents for a prolonged length of time.
CASE 11-14, QUESTION 2: Can G.H. return to using his ibuprofen for pain control?
This question illustrates one of the most difficult therapeutic dilemmas for a patient
taking warfarin. All NSAIDs have the potential to cause gastric irritation by
inhibiting cytoprotective prostaglandins, thereby providing a focus for GI bleeding.
In addition, most NSAIDs inhibit platelet aggregation, which compromises effective
clotting and can lead to bleeding complications.
These effects can increase the risk of hemorrhagic complications significantly in
patients taking warfarin who are prescribed concurrent NSAID therapy. In a
retrospective cohort study of patients age 65 years or older, the risk of
hospitalization for bleeding peptic ulcer disease was approximately 3 times higher
for patients taking concurrent warfarin and an NSAID versus patients taking either
drug alone, and almost 13 times higher than in patients taking neither warfarin nor an
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