Warfarin for DVT: The 3-Month Marker
In our last discussion about warfarin, we focused on KD, a 58-year-old male who was diagnosed with an unprovoked deep vein thrombosis (DVT) in his left leg. Initial treatment for this patient was enoxaparin, coadministered with warfarin, until the international normalized ratio (INR) was stable. KD had an evaluation for thrombophilia, which has returned negative for antiphospholipid syndrome, protein C deficiency, protein S deficiency, factor V Ledien disorder, antiphospholipid antibody syndrome, and antithrombin II deficiency; therefore, there is no identified syndrome present that would mandate long-term anticoagulant therapy.
The 2012 CHEST guidelines recommend at least 3 months of treatment in patients with an unprovoked DVT, followed by an evaluation for the risk–benefit ratio of extended therapy.1
DVT
Unprovoked DVT is a term used to describe the occurrence of DVT in the absence of currently recognized triggers, such as surgery, long-haul travel, immobilization, or trauma. Given sufficient provocation, healthy persons can develop DVT in the post-surgical environment, during immobilization, post-traumatically, or as a result of long-haul travel. On the other hand, if no precipitating factor for DVT is evident, clinicians should be suspicious of underlying procoagulant tendency—as seen in persons with factor V Leiden disorder, antiphospholipid antibody syndrome, and other coagulopathies. Even when a thorough search for thrombophilia turns up negative, persons with unprovoked DVT are recognized to be at greater risk for recurrence, with the underlying suspicion that they may harbor some undetected (or undetectable) coagulopathy. After all, if there was no event that precipitated the DVT, why did they get it in the first place?
The highest risk for extension of DVT and development of pulmonary embolism (PE) is in the first 3 months after the inciting event, hence the recommendation for a foundation warfarin treatment regimen of this duration. In cases like KD, the period of increased risk does not end abruptly at 3 months. Rather, at this point it is important to discuss the relative benefits and risks of continuing anticoagulant treatment.
Bleeding Risks in Perspective
KD was enthusiastic about getting off enoxaparin and progressing to warfarin treatment alone. During the initial few weeks of warfarin treatment, KD was informed that, depending upon his experience with warfarin over the initial 3 months interval, a decision would have to be made about whether to extend treatment with warfarin, aspirin, or other antithrombotics (eg, rivaroxaban, apixaban, or dabigatran). There is no doubt that extending the period of anticoagulation does reduce thrombotic risk; the therapeutic dilemma is how best to balance the recognized risks of major bleeding, combined with the inconvenience and expense of antithrombotic prophylaxis, plus the burden of nonmajor bleeding in comparison to risk reduction of DVT (and potential subsequent PE).
As a yardstick, experts recommend using data from clinical trials as a metric for each of these items in the risk–benefit equation. Hence, warfarin on-treatment risk for major bleeding is estimated at 1% to 2% per year, minor bleeding at 7% to 8.4% per year, and devastating intracerebral bleeding at less than 0.5% per year.1 Bleeding risk scoring systems have been endorsed by European Guidelines (eg, HAS-BLED), but no specific bleeding risk scoring system is advocated by the CHEST guidelines.1
In other words, despite the fact that thrombotic risk is routinely quantified through use of the CHADS2 (or CHADS-VASc) in atrial fibrillation, and we can directly estimate the magnitude of stroke reduction at each CHADS score achievable through antithrombotic therapy, we do not typically perform similar calculations when considering anticoagulant treatment that incorporate bleeding risk scores.
Since risk reduction with antithrombotic therapy in atrial fibrillation is so generous (usually at least 60% reduction in risk for stroke and approximately 25% reduction in mortality), exclusions because of bleeding risk are extraordinary (recent intracranial hemorrhage and thrombocytopenia being the only commonplace exclusions).
In general, bleeding risk increases with advanced age. Additionally, coadministration of NSAIDs or aspirin more than doubles the risk for bleeding as compared to anticoagulation alone.2
The Risk–Benefit Equation
The placebo arms of large clinical trials give us a reasonable picture of the likelihood that our patient KD will sustain another DVT. Untreated, in persons with unprovoked DVT, recurrence rates are generally 5.6% to 8.8%/year.3-5 Recurrent DVT rates untreated may be as high as rates of recurrent stroke in atrial fibrillation patients with a CHADS score of 4 (8.5% per year, untreated).1
However, risks of stroke and risks of recurrent DVT are generally not weighed as equivalent. So we need to talk to KD about recurrence risk (up to 8.8% per year untreated, in his case), risk of major and minor bleeding (as mentioned above), and his general categorization of bleeding risk. As per the CHEST guidelines,1 it is recommended that persons at high risk for bleeding cease warfarin (or other anticoagulant) treatment at the 3-month mark. For persons not at high risk of bleeding, consideration of long-term (indefinite) antithrombotic therapy should be discussed and should take the patient’s preferences, success with anticoagulant treatment, and relative burdens of continuing warfarin into consideration. And the discussion has to be enlarged to consider not only these factors, but other treatment options (eg, novel oral anticoagulants, such as rivaroxaban, or aspirin) as related to warfarin.
Another potential option includes the measurement of the D-dimer. One study showed that an elevated D-dimer measured 3 weeks after discontinuation of anticoagulation therapy was associated with higher risk for venous thromboembolism (VTE) recurrence.6 If the measured level was ≤250 ng/mL, the relative rate of recurrent VTE was 60% lower than if the level was ≥250 ng/mL. Although not recommended as routine practice in all patients, this strategy can be useful to help estimate future risk for recurrent VTE. One important consideration is that pursing this method of risk assessment does require the patient to temporarily discontinue anticoagulation therapy for at least 3 weeks before the D-dimer can be measured, potentially putting a susceptible patient at risk for a DVT or PE.
Outcome of Our Case
Once past the initial few difficulties with enoxaparin administration, KD was able to use warfarin very effectively without any major mishaps. After attaining a therapeutic INR, he maintained an INR within the therapeutic range on each occasion with one exception. In that instance, his supratherapeutic INR was 3.3—sufficiently close to goal, per CHEST guidelines1 no dose adjustment was performed and subsequent INR results remained therapeutic.
KD is very concerned about the potential for PE. Visits to the clinic to check INR have been inconvenient, but he has not been bothered by bleeding or other adversity. He says that he really “feels fine” on the medication. Because of his very favorable history on warfarin, the clinician notes that he could extend the time between visits to as long as 3 months given his history of stability.1 KD was informed about the potential to use a novel anticoagulant instead, but decided it was too “new” of a drug. An alternative option would be the use of daily aspirin, but given KD’s concerns of PE and the reduced efficacy of aspirin in this setting compared to anticoagulation, KD elects to continue with warfarin.
Additionally, the expense of rivaroxaban (approximately $300/month) would be difficult for him; since INR intervals could potentially be extended to 3 months, continuing with warfarin would be the most economical for him.
The decision to continue warfarin need not be carved in stone. That is, if the patient begins to encounter difficulties with warfarin (eg, bleeding, food and drug interactions, and erratic INR levels), switching to another antithrombotic agent or even discontinuing prophylactic treatment is a viable option.
What’s the “Take Home”?
1) Unprovoked DVT should prompt suspicion for underlying thrombophilia.
2) Even if a thrombophilia is not discovered, unprovoked DVT patients are at high risk for recurrences.
3) The CHEST guidelines recommend long-term prophylaxis for DVT recurrence in patients with unprovoked DVT who find the use of antithrombotic therapy not to be too burdensome, have not experienced bleeding problems, nor have difficulty in maintaining a therapeutic INR—unless they are recognized to be at high bleeding risk.
4) There is no “one-size-fits-all” at the conclusion of the initial 3-month prophylaxis interval after DVT. Although this interval of treatment is sufficient for patients with provoked DVT (eg, post-surgical, post-traumatic, transient immobilization), unprovoked DVT intimates thrombotic tendency—which may merit indefinite treatment. ■
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).
2.Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-953.
3.Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
4.Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708.
5.Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
6.Eichinger S, Minar E, Bialonczyk C, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA. 2003;290(8):1071-1074.