Anticoagulation Treatment for DVT

History

KD is a 58-year-old male who was diagnosed with an unprovoked deep vein thrombosis (DVT) in his left leg; he was hospitalized late on a Sunday. Upon hospitalization, he received a therapeutic dose heparin infusion and was discharged the following day (Monday) having received his first 5 mg warfarin dose. He was instructed to take warfarin 5 mg daily, enoxaparin 1 mg/kg subcutaneously twice daily, and to schedule an appointment with his primary care physician within 2 to 4 days.

Presentation

KD presents to your office Friday morning having taken 4 doses of warfarin 5 mg (first dose in the hospital on Monday, then 3 doses at home each evening thereafter). His only other prescription is amlodipine 5 mg daily for high blood pressure.

A hypercoagulable work-up ordered in the hospital (protein C, protein S, factor V Leiden, antithrombin, and antiphospholipid antibody) is still pending. The patient’s international normalized ratio (INR) today is 1.6 (goal 2 to 3). 

How long should he continue enoxaparin and how should it be safely discontinued?
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Discussion

The goal of initial anticoagulant treatment of DVT is to prevent propagation of the existing DVT and prevent development of a new venous thromboembolic (VTE) event, such as a pulmonary embolus. Because development of anticoagulant effects of warfarin takes at least 5 days for most patients, the desire for more immediate anticoagulation requires a more rapid-acting anticoagulant. 

Heparinoids include enoxaparin, heparin, fondaparinux, and others. The most commonly used heparinoids are heparin infusion (for inpatients, when essentially immediate anticoagulant impact is desired) and enoxaparin (administered subcutaneously, when prompt—within a few hours—anticoagulation is desired). A typical pattern of use is to initiate heparin infusion for 24 hours and transition to a subcutaneous heparinoid for sufficient time to protect the patient from further development/propagation of DVT until full anticoagulant effects of warfarin have been attained. CHEST recommend at least 5 days of heparinoid therapy in all patients following a VTE event.¹ 

Of note, although rapidly active, the novel oral anticoagulants (eg, apixaban, dabigatran, rivaroxaban) are not currently recommended to be used as bridge therapy in place of a heparinoid due to a lack of evidence for use in this role.

Enoxaparin

Enoxaparin is the most commonly used heparinoid agent due to its generic availability and clinical experience, although heparin or fondaparinux could also be recommended. Fondaparinux would be preferred to heparin and enoxaparin in patients with a history of heparin-induced thrombocytopenia. 

Enoxaparin does not require routine laboratory monitoring and leads to consistent anticoagulant effects using weight-based dosing. Per the package-insert, enxoaparin can be dosed at 1 mg/kg twice daily or 1.5 mg once daily. The 2012 CHEST guidelines recommend an alternative once-daily dose of 2 mg/kg.¹ Head-to-head studies have not been conducted to determine the relative safety and efficacy of each regimen but we prefer the 1 mg/kg twice daily-dose. The ambiguity of various dose recommendations, combined with the fact that there is a paucity of data and dosing recommendations in obese persons, leads to this perspective. If factors such as cost are a significant influencing factor, then we may consider once-daily dosing and prefer to use the package insert recommended 1.5 mg/kg dose as it has been studied clinically. 

Heparinoid With Warfarin

What is the “magic” about 5 days co-administration of heparinoid with warfarin? More accurately, we should state that heparioid should be administered for at least 5 days. As previously mentioned, warfarin usually requires 5 to 7 days to completely dissipate the impact of factor II, the clotting cascade factor with the longest half-life. In the setting of DVT, we use the parenteral heparinoid to ensure immediate and sustained anticoagulation until warfarin has manifested an adequate and stable effect on clotting factors as measured by an INR of at least 2.0, at which point the heparinoid can be discontinued. 

Note: Heparinoid use is burdensome for most patients. A subcutaneous injection is required 1 to 2 times daily, local injection site reactions are common, and subcutaneous hemorrhage—which can be unsightly as well as painful—is also common. Furthermore, the medication is a substantial expense (enoxaparin 80 mg/d x 10 days = approximately $300 retail). 

Therefore, our therapeutic goal for VTE is to attain and maintain anticoagulation as quickly as possible, and then to transition to long-term oral anticoagulation promptly to avoid the adverse effects, inconvenience, and expense of heparinoids. As recommended in the CHEST guidelines,¹ heparinoid can be discontinued when the patient has maintained a therapeutic INR for at least 24 hours. 

Treatment

We have found that the most efficient way of prescribing heparinoid is in amounts sufficient to provide dosing for 2 to 3 weeks. In the best of all worlds, patients might only need as few as 3 to 4 doses, however, since it is much more common to have to perform multiple warfarin adjustments before arriving at sustained appropriate anticoagulation, we want patients to have sufficient heparinoid on hand less they run out and incur risk of VTE recurrence. Additionally, as the majority of patients have prescription drug insurance, they will be required to provide a copay when picking up the prescription from the pharmacy. This copay is often the same amount regardless of supply order (eg, 1 week or 3 weeks). 

KD’s INR of 1.6 (at day 4) is a commonly encountered result. For readers who have not read earlier segments of our educational vignettes on warfarin, this early observation point is used for 2 reasons: 

1. To identify “hot reactors” (persons who are very sensitive to warfarin, and might become meaningfully
supratherapeutic on the “typical” 5 mg/d dosing) before they get into trouble. 

2.  To gain insight into the “slope” of response the patient might experience. At this point we feel safe that he is not a person who is highly sensitive to warfarin and that we can ask him to return in 3 to 4 days, at which point the maximum effect of this dose of warfarin should be measurable. Because he has not yet attained a therapeutic INR, he cannot yet discontinue enoxaparin subcutaneously. 

KD returns to clinic in 3 days (Monday) and his INR is now 2.0 (day 8 of treatment). Should his enoxaparin be discontinued at this time?

Heparinoid Therapy Timeline

The CHEST guidelines recommend at least 5 days of heparinoid therapy and a therapeutic INR for at least 24 hours prior to discontinuation of bridge therapy with the heparinoid.¹ KD has received more that 5 days of enoxaparin, so this criteria has been satisfied. His INR is considered to be therapeutic (goal 2 to 3), but we need to confirm that he has a therapeutic INR for 24 hours. In our experience, 3 common situations arise when the first therapeutic INR is achieved that warrant further discussion when considering how best to confirm a therapeutic INR and discontinue bridge therapy.

1. The first therapeutic INR is only minimally therapeutic (INR 2.0-2.3).

As the first therapeutic INR value is minimally therapeutic, attention must be paid to the wording of the CHEST recommendation: therapeutic INR for at least 24 hours. With the INR being so minimally above the desired threshold of effectiveness, clinicians would rightly be concerned that small changes in lifestyle (eg, dietary vitamin K) might lead to a clearly subtherapeutic INR quickly. Patients should be reminded at this point of factors which reduce INR, to avoid any changes in diet or medication (even over-the- counter), and to limit the chances for a resulting subtherapeutic INR (and need for the continuation of bridge therapy). Most often, the patient will return the next day with a still-therapeutic INR. Enoxaparin may be discontinued at that time.

2. INR is therapeutic (INR 2.4-3.0).

Similar to situation 1, the INR is therapeutic but there is a small chance that the INR could be subtherapeutic in the next 24 hours if the patient makes prominent changes in his vitamin K intake. We have a greater “safety margin” here than in the first scenario, and it is unlikely that any dietary change, save a very large increase in vitamin K-contianing food, would produce a subtherapeutic INR by tomorrow. Additionally, a missed warfarin dose could also lead to a subtherapeutic INR. As in the previous scenario, most often the patient will return the next day with a still-therapeutic INR. At that time, enoxaparin may be discontinued. 

3. INR is supratherapeutic (INR ≥3.0).

The purpose of the CHEST guideline¹ recommendation—that the INR be therapeutic for 24 hours—was to ensure safe discontinuation of heparinoid, as well as safe continuation of warfarin. Unless we were to administer an agent known to promptly reduce the INR (eg, vitamin K in the form of phytonadione), we are essentially certain that the patients INR will be at least therapeutic tomorrow. Indeed, being foolishly insistent on the technicality that the INR will confirm to be therapeutic 24 hours later would not only delay the discontinuation of enoxaparin, but would expose the patient to unnecessary risk of continuing enoxaparin in the face of a supratherapeutic INR. Therefore, discontinuation of enoxaparin at this point is sensible for optimizing patient safety, with the knowledge that the requirement for 24-hour stability of the INR will be tacitly met. 

For scenario 3, we would elect to discontinue enoxaparin bridge therapy and continue with warfarin therapy alone. Depending upon how far outside the therapeutic range the INR is, warfarin dosing may also have to be adjusted in order to lower the INR down into the therapeutic range. For scenarios 1 and 2, we would recommend to continue bridge therapy with enoxaparin and repeat the INR the following day to confirm that a therapeutic INR had been maintained for at least 24 hours. Since the patient would have more than a 1-week supply at home, in the event the INR became subtherapeutic, enoxaparin could be continued on the following clinic day without the need to purchase a new supply. 

Outcome of Our Case

KD fits into scenario 1 and therefore, he would be asked to continue enoxaparin and warfarin and return to clinic the following day for INR reassessment. 

KD returns on Tuesday morning (day 9), hoping to discontinue his enoxaparin today based upon the therapeutic INR yesterday on day 8. His INR this morning is 2.1, and he has not yet administered his morning enoxaparin dose (if he had an afternoon or evening appointment he should take his morning dose of enoxaparin). He is happy to be informed that he can now discontinue enoxaparin. He has met the CHEST criteria for discontinuation—at least 5 days of heparinoid therapy and a therapeutic INR for at least 24 hours.

What’s The “Take Home”?

1. Bridge therapy refers to the use of rapid-acting heparinoids to attain satisfactory short-term anticoagulation until long-term efficacy with oral anticoagulants can be achieved.

2. Bridge therapy with enoxaparin should be dosed at 1 mg/kg twice daily in most scenarios.

3. Bridge therapy should be continued for at least 5 days and the INR should be therapeutic for at least 24 hours prior to discontinuation of bridge therapy.

4. In scenarios where the INR is therapeutic at day 5, we prefer to confirm maintenance of a therapeutic INR for 24 hours with a repeat INR the following day while bridge therapy is continued.

5. If the first INR therapeutic is actually supratherapeutic (INR >3.0), bridge therapy can be safely discontinued since we are confident that the INR 24 hours later will be therapeutic—thereby tacitly fulfilling the CHEST guidance principle.■

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