Bridge Therapy for Venous Thromboembolism

In our experience, we support providing bridge therapy to those deemed at moderate or high risk for venous thromboembolism (VTE) when anticoagulation will have to be discontinued. Determining risk is an imperfect science that relies heavily on clinical judgment. As heparinoid therapy is relatively safe (<1% risk for major hemorrhage), readily available (generically available as enoxaparin, although absence of prescription insurance will lead to significant acquisition costs), and easy for the patient to administer after counseling and education, the potential benefits in terms of VTE risk reduction likely outweigh the risks of bleeding. 

However, for those at low to moderate risk for VTE and/or those who have a higher risk for bleeding, who are expected to have difficulty administering the injections, who report problematic negative experiences with prior heparinoid use, or who would experience significant financial difficulties obtaining the heparinoid, we feel it is reasonable to withhold heparinoid therapy. As with the decision to initiate or continue warfarin therapy, decisions surrounding bridge therapy are patient-specific and should be evaluated on a case-by-case basis. 

A Case Study 

Our patient, KD, cannot be stratified for risk through the CHADS2 score because his indication for warfarin was deep vein thrombosis (DVT). Given that his estimated risk for recurrent VTE is roughly 6% to 8% based on recent clinical trial data, he would be stratified as moderate risk and would be considered for heparinoid therapy. He is highly motivated to avoid recurrent VTE events and therefore, elected to continue with indefinite anticoagulation after completing 3 months of treatment after his initial unprovoked DVT. We believe that he will be adherent to the treatment regimen to enhance the likelihood that the benefits will outweigh risks.

As opposed to simply discontinuing warfarin 5 days prior to the procedure and starting bridge therapy, we prefer to measure the international normalized ratio (INR) 5 to 7 days prior to the procedure to guide both warfarin discontinuation and heparinoid initiation. Why? 

In 1 scenario,  KD came in with an INR of 3.6 on the day he was planning to discontinue warfarin. If, as per the general recommendation, we suggest that KD not take his dose of warfarin today and begin bridge therapy, we are exposing KD to the combined risk of bleeding from his already supratherapeutic INR plus the anticoagulant effects of the heaprinoid. Therefore, it appears wiser to hold 1 to 2 doses of warfarin and then begin the heparinoid. 

So, if KD sees us on Monday, we would ask him to omit the dose of warfarin today and tomorrow (Monday and Tuesday) and then initiate enoxaparin beginning on Wednesday morning, by which time we can be confident that the INR should have become lowered to minimize his risk for excessive anticoagulation and bleeding.

Timeline for Bridge Therapy Initation

For those patients with a therapeutic INR, especially if the INR is at the low end of the therapeutic range, discontinuing warfarin 5 days prior to the procedure and starting the heparinoid is sufficient. If KD had an INR of 2.2 on Monday, we would ask that he omit his Monday dose of warfarin and begin his enoxaparin Monday evening at the time he would have taken his warfarin dose. As the goal of hepainoid therapy in this setting is to minimize (or avoid completely) a period of subtherapeutic anticoagulation, the heparinoid should be started while the anticoagulation is still therapeutic. If the heparinoid is held until the INR is subtherapeutic, the patient will be exposed to the risks of VTE, which is the goal and purpose of bridge therapy. However, starting the heparinoid when the INR is supratherapeutic increases the risk of bleeding as the patient would be “double-anticoagulated.”

The question then arises: If we are concerned with double anticoagulation, then why would we not wait for INR to become subtherapeutic prior to initiating the bridge therapy? 

While this is a reasonable question, remember that the overall goal of bridge therapy is to minimize risk for VTE by providing therapeutic anticoagulation and minimizing (or eliminating) periods of subtherapeutic anticoagulation. In an ideal world, we could accurately predict the time course of the INR reduction following discontinuation of warfarin and pinpoint the time when the INR becomes subtherapeutic to start the heparinoid. 

However, given that every patient responds differently to the therapeutic effects of warfarin, it is likely this variability holds true during discontinuation. Outside of serial INR monitoring, there is not a reliable way to accurately predict an INR trajectory upon warfarin discontinuation that can be uniformly applied to all patients. This is why we prefer to first obtain an INR prior to determining when bridge therapy can be initiated. 

In order to eliminate periods of subtherapeutic anticoagulation, bridge therapy will have to be started at a time when the INR is therapeutic; to minimize the risks for bleeding as much as possible, the heparinoid should be started with the INR as close as possible to the lower end of the therapeutic range. This initial period of double anticoagulation is an important consideration in the initial risk/benefit assessment and the potential benefits of initiating bridge therapy to reduce the risk for VTE should outweigh the risks of bleeding. As mentioned in the “Periprocedural Comadin Management,” (Consultant, August 2014, page 641), there is no “no-risk” path when initiating bridge therapy and minimizing bleeding risks but waiting until the INR is subtherapeutic prior to starting the heparinoid puts the patient at risk for VTE events.

If on the presurgical visit day (5 to 7 days preoperatively) the INR happens to be subtherapeutic, the heparinoid should be started immediately in order to restore prompt and full therapeutic anticoagulation, and continued until the procedure. The warfarin should also be held and not restarted; there is limited value in adjusting the warfarin dose in order to raise the INR as it will have to be held for the procedure anyway 1 or 2 days following this INR evaluation.

Post-Procedure Management

Postoperatively, we suggest rechecking the INR approximately 5 days after warfarin is restarted. This early INR follow-up is intended to minimize the duration of the need for heparinoid therapy as much as possible, while ensuring that the patient does not incur a supratherapeutic INR. 

Why would the patient be at risk of a supratherapeutic INR if he goes right back to the dose he was receiving before that lead to a therapeutic INR? Surgical stress, changes in diet and bowel function, and medications administered perioperatively might each contribute to an altered responsiveness to the very same warfarin dose the patient was taking before, hence the need for caution. Although the full anticoagulant effects of warfarin are often realized within the first 5 to 7 days, it is not uncommon for the INR to take longer than 7 days to return to the therapeutic range following discontinuation for a surgical procedure. 

Once a therapeutic INR is achieved, the decision to stop bridge therapy is not as clear as would be expected. In patients with a recent VTE receiving bridge therapy, CHEST recommends patients have a therapeutic INR for at least 24 hours prior to discontinuing bridge therapy. Therefore, in patients with a recent VTE (<3 months ago), we would recommend this same strategy be employed in the setting of warfarin discontinuation for a procedure; the risk for VTE decreases as time progresses and as these patients are close to their initial event the risk for a subsequent event would likely outweigh the potential risks for bleeding of 1 additional day of heparinoid therapy. 

This same strategy should likely be applied to those patient’s deemed at a high risk for VTE due to their significant risk (>10%), such as those with a CHADS2 score of 5 to 6, those with a mechanical mitral valve, or with underlying coagulopathies (eg, antiphospholipid syndrome). 

A corollary to this rule is a patient who presents with a supratherapeutic INR after 5 to 7 days of combined warfarin and heparinoid will certainly be expected to have an INR that is at least therapeutic the following day, hence a next day confirmation becomes superfluous and may be omitted, and the heparinoid may be discontinued at the time of identification of the supratherapeutic INR, so as not to expose the patient unnecessarily to the potential adverse effects of both overanticoagulation with warfarin combined with heparinoid-related bleeding risk.

For patients receiving long-term warfarin therapy for the secondary prevention of DVT/pulmonary embolism (outside of the initial 3 month treatment period) or condition such as atrial fibrillation (with CHADS2 score of 2 to 4), the risk for recurrent VTE is likely sufficiently low that once a therapeutic INR is obtained, the heparinoid therapy can be discontinued at that time without the need for repeat confirmation of a therapeutic INR. 

Although the risk of bleeding with 1 additional day of heparinoid is likely small, the need for documentation of a continued therapeutic INR is not as high given the low risk for subsequent VTE. Confirming that there have been no changes in diet, medications, or other factors that can lower the INR will be paramount to ensure the absence of any potential factor that may lead to a subtherapeutic INR in the next 24 hours. 

If concerns are present, the INR should be reassessed in 24 hours to confirm maintenance of the therapeutic INR. It should be noted that evidence does not exist to support or refute this strategy and it has not been compared to the strategy of confirming a therapeutic INR for 24 hours. Given the burden of heparinoid therapy and INR monitoring, this strategy may be considered for select patients. 

Outcome of the Case

KD would be considered to be at moderate risk as his last VTE was over 3 months ago and his risk for recurrence is between 5% and 10%. His INR today (Monday) is 2.8 and his procedure is scheduled for the following Monday. Because he is motivated to attain maximal risk reduction, we would order 21 days of enoxaparin dosed at 1 mg/kg twice daily, asking him to omit his Wednesday night dose of warfarin and begin enoxaparin administration at that time. We would recheck his INR the Friday following his procedure (5 days post-procedure) to ensure his INR has not become supratherapeutic and to minimize the time he has to take both enoxaparin and warfarin. Given his moderate risk for VTE, we would consider discontinuing enoxaparin upon his first confirmed therapeutic INR value following his procedure.

The Take-Away

1. The INR should be checked approximately 5 days prior to the procedure to guide warfarin discontinuation and heparinoid therapy initiation.

2. In those with a supratherapeutic INR, warfarin should be omitted for 1 to 2 days until the INR has decreased sufficiently to limit the risk of double anticoagulation with starting heparinoid therapy concomitantly. Those with a subtherapeutic INR should have heparinoid therapy promptly initiated.

3. The INR should be checked 5 to 7 days following warfarin reinitiation. For those at high risk for recurrent VTE, the INR should likely be confirmed to be therapeutic for 24 hours prior to heparinoid discontinuation. Patients with a moderate risk may be safely transferred off heparinoid therapy following the first confirmed therapeutic INR. 

4. In those with a supratherapeutic INR, the heparinoid should be stopped promptly regardless of VTE risk due to the risks of bleeding. ν

Eric A. Dietrich, PharmD, BCPS, graduated from UF College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He now works for the UF Colleges of Pharmacy and Medicine. 

Louis Kuritzky, MD, is a family physician affiliated with the University of Florida Family Medicine Residency Program, where he commonly co-manages warfarin cases with his colleagues.

References:

1. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):299S-339S.

2. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: CHEST Evidence-Based Clinical Practice Guidelines. 2012;141(2 Suppl).