Management of Anticoagulation for Venous Thromboembolism
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A 74-year-old man presents to the emergency department with progressive shortness of breath for the previous two days. His past medical history is notable for hypertension and coronary artery disease status post remote bare metal left anterior descending (LAD) artery stent placement. Outpatient medications include low-dose aspirin, atenolol, and lisinopril. Initial physical examination reveals normal vital signs and is otherwise unremarkable. Labs are notable for normal renal function, N-terminal pro b-type natriuretic peptide (NT-proBNP) of 2378, and troponin-T of 0.08. Chest radiograph is without any abnormalities; electrocardiogram shows normal sinus rhythm with new T-wave inversions in the early precordial leads as compared to prior. Subsequent CT angiogram demonstrates large bilateral pulmonary emboli. Of note, the patient has no history of trauma, immobilization, recent surgery, hypercoagulable states, malignancy, or hemorrhagic events.
Based on current evidence and guidelines, which of the following anticoagulation strategies would lead to the lowest rate of recurrent venous thromboembolism, without exposing the patient to excessive risk of clinically significant bleeding?
The correct answer is: E. Novel oral anticoagulant indefinitely, with periodic reassessment of risk-benefit profile of anticoagulation.
Venous thromboembolism (VTE), which encompasses both deep venous thrombosis (DVT) and pulmonary embolism (PE), affects at least 700,000 people annually in North America, and is the third most common cardiovascular disease following myocardial infarction and stroke.1-3 The standard treatment for VTE has been low molecular weight heparin (LMWH) bridge to a vitamin K antagonist, typically warfarin, with goal INR of 2-3.4,5 More recently, several novel anticoagulants, including dabigatran, rivaroxaban, apixaban, and edoxaban, have emerged as suitable alternatives for management of VTE. Designing a treatment strategy requires selecting the appropriate anticoagulant and optimal duration of anticoagulation, with the ultimate goal of minimizing both the incidence of recurrent VTE and clinically significant bleeding events.
Fortunately, there is a host of new evidence to help guide the choice of anticoagulant, driven in large part by growing interest in the aforementioned novel agents, which do not require routine monitoring of coagulation parameters. Five clinical trials have recently been completed that directly compare the efficacy of individual novel anticoagulants with standard therapy for VTE.6-10 All of these trials were designed as non-inferiority studies with respect to the primary endpoint of recurrent VTE. The principal safety outcome measured was the incidence of major bleeding events or clinically significant non-major bleeding.
Dabigatran, an oral direct thrombin inhibitor, was the first of the novel anticoagulants to be investigated in patients with VTE in the RE-COVER trial.6 In this study, patients with acute VTE initially managed with parenteral anticoagulation were randomized to receive dabigatran or warfarin for a total of six months. The primary endpoint was the six-month incidence of recurrent symptomatic, objectively confirmed VTE and related deaths. Dabigatran proved to be non-inferior to warfarin in regard to the primary efficacy outcome and there was no statistically significant difference between the two groups with respect to major bleeding episodes. However, dabigatran demonstrated a lower rate of any clinically significant bleeding events when compared to warfarin.
Rivaroxaban, an oral factor Xa inhibitor, was studied in both the EINSTEIN-DVT7 and EINSTEIN-PE8 trials. In EINSTEIN-DVT, patients with acute DVT were randomized to rivaroxaban or LMWH bridge to warfarin for a period of three to 12 months, with duration determined at the discretion of the treating physician. The study showed that rivaroxaban was non-inferior to LMWH/warfarin in regard to recurrent VTE, and clinically significant bleeding events occurred at equivalent rates between the two groups. Therefore, while rivaroxaban has similar efficacy in prevention of recurrent VTE in patients with acute DVT, there is no clear improvement in the safety profile of the drug relative to standard therapy. EINSTEIN-PE randomized patients with PE (with or without concurrent DVT) to the same treatment arms as in EINSTEIN-DVT. Again, this trial demonstrated non-inferiority of rivaroxaban relative to standard therapy with respect to rates recurrent symptomatic VTE. Despite similar rates of clinically significant bleeding events between the two arms, there was statistically significant reduction in incidence of major bleeding in the rivaroxaban group, suggesting a possibly improved risk-benefit profile as compared to LMWH/warfarin.
The AMPLIFY9 trial investigated apixaban, another oral factor Xa inhibitor, with respect to treatment of acute VTE over a fixed period of six months. Apixaban was non-inferior to the LMWH/warfarin arm in regard to incidence of recurrent VTE and VTE-related mortality, and demonstrated a statistically significant reduction in the incidence of clinically significant bleeding events.
Lastly, edoxaban is an oral factor Xa inhibitor that was recently investigated in the Hokusai-VTE trial.10 In this study, patients with acute VTE initially treated with a heparin product (unfractionated heparin or LMWH) were randomized to receive edoxaban or warfarin for three to 12 months, with the duration determined at the discretion of the treating physician. Edoxaban showed non-inferiority to warfarin with respect to the primary outcome of symptomatic recurrent VTE. Furthermore, the edoxaban group had a significantly lower rate of major bleeding or clinically relevant non-major bleeding.
The duration of anticoagulation is another important consideration in developing a treatment strategy for VTE. The two most significant factors in making this clinical decision are the presence of underlying risk factors that may have provoked VTE and the individual patient's bleeding risk. Examples of reversible precipitating risk factors include surgery, trauma, immobilization, acute medical illness, oral contraceptive use, post-menopausal hormone replacement and pregnancy. All patients with VTE merit at least three months of anticoagulation, since the risk of recurrent events is highest during this early period.3-5 For a provoked VTE event, defined by presence of one of the aforementioned transient risk factors, anticoagulation may be stopped after three months. In patients whose VTE was thought to be provoked by active malignancy, patients should be anticoagulated until the cancer is considered to be cured or under control. Finally, in cases of VTE without a clear trigger, anticoagulation should be continued indefinitely so long as the risk-benefit profile of therapy is favorable. Determination of the risk-benefit profile of anticoagulation is largely left to the discretion of the treating clinician, but can be aided by clinical scoring methods, such as HEMORR2HAGES,11 RIETE,12 and HAS-BLED.13 However, it should be noted that the HEMORR2HAGES and HAS-BLED scoring systems were studied in atrial fibrillation and have not been validated for patients with VTE.
Since our patient has no predisposing risk factors for VTE, the PE can be considered unprovoked. No significant risk factors for hemorrhage are present based on the above scoring methods, making the patient a low-risk candidate for anticoagulation. Therefore, he would merit indefinite anticoagulation with periodic reassessment of his risk-benefit profile.
Choice A is not the best answer since LMWH/warfarin strategy leads to increased bleeding risk relative to apixaban or edoxaban, and possibly increased bleeding risk relative to dabigatran and rivaroxaban. Furthermore, anticoagulation should not be limited to a firm endpoint of six months duration, as mentioned above.
Choices B, C, and D raise the possibility of managing the patient's PE with novel anticoagulants for fixed time periods of two, three, and six months, respectively. These choices are not optimal by similar logic in regard to duration of anticoagulation. Acute VTE merits a minimum of three months of anticoagulation, regardless of predisposing factors. For our patient, extended therapy with regular re-evaluation of risks and benefits is warranted.
Based on the trial data presented above, rivaroxaban and dabigatran have possibly improved bleeding profiles as compared to standard therapy, whereas apixaban and edoxaban have statistically significant improvements in bleeding risk relative to conventional treatment. Dabigatran, rivaroxaban, and apixaban have all been FDA-approved for management of VTE and long-term prevention of VTE, with apixaban gaining approval most recently in August 2014. Edoxaban, however, has not been approved for any indication outside of Japan where it has been available only for VTE prevention since 2011. Taking all aspects into consideration, the best answer is choice E, treatment with a novel oral anticoagulant indefinitely, with periodic reassessment of risk-benefit profile of anticoagulation.
- Heit JA. The epidemiology of venous thromboembolism in the community: implications for prevention and management. J Thromb Thrombolysis 2006;21:23-9.
- White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:Suppl 1:I-4–I-8.
- Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012;379:1835-46.
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:Suppl: e419S-e494S.
- Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788-1830.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
- The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.
- The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808.
- The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.
- Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713–19.
- Ruiz-Gimenez N, Suarez C, Gonzalez R, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100:26–31.
- Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093-1100.