It’s a new era in anticoagulant therapy

Dr. Lockwood, editor in chief, is Dean of the College of Medicine and Vice President for Health Sciences at The Ohio State University, Columbus, Ohio. Contact him at DrLockwood@advanstar.com.

A 36-year-old G3P3002 presents with a very swollen erythematous left leg 2 days after discharge following a cesarean delivery for arrest of descent, macrosomia, and chorioamnionitis. She had diet-controlled gestational diabetes, her body mass index (BMI) is 35, and she has bilateral lower extremity varicose veins and clear evidence of superficial thrombophlebitis in the left leg. Compression venous ultrasound (CU/S) reveals a large femoral vein thrombosis extending into the pelvis.

The patient is begun on enoxaparin 1 mg/kg subcutaneously twice daily. However, because of evidence of possible iliofemoral arterial compromise, she undergoes thrombolytic therapy with alteplase (Activase) 100 mg IV given over 2 hours. About 8 hours later, the patient experiences a significant postpartum hemorrhage requiring multiple transfusions and uterotonic therapy. She does not plan to breastfeed, was noncompliant with glucose monitoring during the pregnancy and, in view of her recent history, is very concerned about having another hemorrhage. Therefore, she is begun on apixaban (Eliquis) 5 mg orally twice a day.

Although this particular presentation is rather complex and relatively uncommon, venous thrombosis is not uncommon. It behooves ob/gyn practitioners to keep current with the latest agents and strategies for treating venous thromboembolic (VTE) events in both pregnant and nonpregnant women.

Prevalence

The past few decades have witnessed an increase in the occurrence of antepartum VTE and a decrease in the prevalence of postpartum thrombotic events.^1,2 I suspect this paradox reflects the opposing influences of the obesity epidemic and the increased use of puerperal prophylaxis. In nonpregnant adult women, occurrence of VTE rises exponentially with age.

The annual incidence of acute pulmonary embolism (PE) and deep venous thrombosis (DVT) increases from 7 and 14 per 100,000, respectively, in women aged 30–39 years, to 62 and 99 per 100,000 at ages 60–69 years, to 140 and 303 per 100,000 for women aged ≥80 years.³  The lifetime risk of VTE is about 5%.⁴

Superficial thrombophlebitis is relatively common in pregnant and nonpregnant older women with varicose veins, and is associated with coexistent DVT in about 10% of cases,⁵ and up to 53% when the saphenous vein is affected.⁶

Diagnosis

The mainstay of DVT diagnosis in both pregnant and nonpregnant states is CU/S. D-dimer assessment is used as a potential rule-out test in low-risk nonpregnant women. For diagnosing PE in nonpregnant women, the standard approach is to start with D-dimer testing when risk scoring assessment suggests a low risk for PE and computerized tomographic (CT) pulmonary angiography for D-dimer positive low risk and all high-risk patients.

However, recent thinking has changed regarding the optimal diagnostic work-up of suspected PE in pregnancy. An expert panel that included fellows of the American College of Obstetricians and Gynecologists (ACOG) and members from other relevant professional societies recommended CU/S as the initial study in hemodynamically stable patients with suspected PE, but only if they had signs and symptoms of a possible DVT.⁷ Chest x-ray was recommended as the first radiation-associated diagnostic test and, if negative, subsequent ventilation/perfusion scanning. However, if the chest x-ray is abnormal, the panel recommended proceeding directly to CT pulmonary angiography. This approach maximizes diagnostic efficacy while minimizing breast irradiation.

New anticoagulant treatments

A growing number of highly effective agents are now available to treat acute VTE in nonpregnant adults and/or provide long-term prophylaxis against recurrence. In patients with normal renal function, low-molecular-weight heparin (LMWH) is preferred over unfractionated heparin because the former improves survival, reduces VTE recurrence, and lowers the risk of hemorrhage.⁸ Moreover, in non-pregnant patients, LMWH treatment can usually be conducted in outpatient settings, reducing cost.⁴

This initial LMWH therapy traditionally has been followed by oral anticoagulation with warfarin for at least 3 months. Genetic variability in response to warfarin, however, necessitates meticulous surveillance of INR values with frequent dose adjustment to mitigate risk of hemorrhage, a process which can be time-consuming and expensive.

Because of the high level of inter-patient variability in response to both LMWH and warfarin and the nonspecific nature of their anticoagulant effects, a variety of new highly specific oral antithrombotic agents have been developed with very predictable pharmacokinetics, simplified dosing regimens, and less risk of bleeding. While these agents are not currently reversible, they have relatively short half-lives. Two Factor Xa inhibitors are available: rivaroxaban (Xarelto) and apixaban. Rivaroxaban displays efficacy comparable to LMWH/warfarin in treating acute VTE, and can be used for long-term maintenance.⁴ Moreover, it appears to be associated with fewer bleeding sequelae9 and is FDA-approved for treatment of acute VTE. These characteristics, coupled with its ease of administration and lack of monitoring requirements, make rivaroxaban an attractive choice for the initial treatment of VTE and subsequent maintenance therapy. However, while substantial savings result from the absence of monitoring requirements, rivaroxaban is far more expensive than generic warfarin ($265 vs $6 per day).¹⁰

Long-term anticoagulation with apixaban appears to reduce the risk of recurrent VTE without increasing risk of major bleeding,¹¹ and, although it is not yet FDA-approved for this indication, a recent clinical trial found it had comparable efficacy and greater safety compared with LMWH/warfarin for treatment of acute VTE.¹² It is, however, comparable to rivaroxaban in cost.¹⁰

Dabigatran etexilate (Pradaxa) is an oral anti-thrombin agent that appears to be superior to warfarin in efficacy and safety for long-term anti-thrombotic maintenance therapy.¹³ However, initial reports suggested a modestly higher risk of relatively rare acute coronary symptoms.¹³ Although not FDA-approved for treatment of acute VTE, dabigatran has comparable efficacy and cardiac safety as well as lower risk of bleeding compared with LMWH/warfarin, according to a recent study.¹⁴ Dabigatran is priced similarly to rivaroxaban and apixaban.¹⁰ Unfortunately, the safety and utility of these agents in pregnancy is unexplored. Thus, their use must be limited to the postpartum period.

Thrombolysis

The perceived value of thrombolysis has ebbed and flowed. In the setting of DVT it may reduce the occurrence of post-thrombotic syndrome, which can occur in up to 40% of cases, but at the cost of increased hemorrhagic sequelae.⁴ In the nonpregnant state, thrombolysis should be used only in patients with DVT at high risk of limb loss or in patients with PE in the setting of severe cardiopulmonary compromise.⁴ In pregnancy, thrombolysis has been associated with rates of 1.2% maternal and 5.8% fetal mortality, as well as an 8.1% risk of maternal hemorrhage.¹⁵ Catheter-directed therapy with stenting may increase patency and reduce the risk of bleeding in both the antepartum and postpartum state.^16,17

Treat superficial thrombophlebitis with anticoagulation

Traditional approaches to treating superficial thrombophlebitis included bedrest, heat, elevation, and analgesia, but not heparin. Although there is no evidence that bedrest is helpful, non-steroidal anti-inflammatory drugs may lower rates of extension and recurrence.¹⁸ Moreover, treatment with fondaparinux (Arixtra) (2.5 mg subcutaneously daily for 45 days) has now been associated with lower rates of concomitant VTE, local extension, and recurrence, with low rates of bleeding.¹⁸

Take-home message

The past few years have seen a simplification of the diagnostic work-up of VTE in nonpregnant women, reduced radiation exposure in evaluation of pregnant women for suspected PE, and development of powerful new oral agents for treatment of VTE and prevention of its recurrence. These agents offer comparable efficacy, enhanced simplicity of use, and reduced risk of bleeding compared with traditional LMWH/warfarin. What is needed now are careful cost-comparison studies that incorporate savings accrued from the absence of monitoring and the lower occurrence of complications versus the increased cost per dose of these new treatments. Moreover, the safety and efficacy of these agents in pregnancy has yet to be established.

References

1. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143(10):697–706.

2. Kane EV, Calderwood C, Dobbie R, Morris C, Roman E, Greer IA. A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005. Eur J Obstet Gynecol Reprod Biol. 2013;169(2):223–229.

3. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5):933–938.

4. Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA. 2014;311(7):717–728.

5. Di Nisio M, Middeldorp S. Treatment of lower extremity superficial thrombophlebitis. JAMA. 2014;311(7):729–730.

6. Leon L, Giannoukas AD, Dodd D, Chan P, Labropoulos N. Clinical significance of superficial vein thrombosis. Eur J Vasc Endovasc Surg. 2005;29(1):10–17.

7. Leung AN, Bull TM, Jaeschke R, et al; ATS/STR Committee on Pulmonary Embolism in Pregnancy. An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med. 2011;184(10):1200–1208.

8. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010;(9):CD001100.

9. Prins MH, Lensing AW, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.

10. New oral anticoagulants for acute venous thromboembolism. JAMA. 2014;311(7):731–732. doi: 10.1001/jama.2014.202.

11. Agnelli G, Buller HR, Cohen A, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708.

12. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.

13. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. NEngl J Med. 2013;368(8):709–718.

14. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators*. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–772.

15. Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv. 1995;50(7):534–541.

16. Herrera S, Comerota AJ, Thakur S, et al. Managing iliofemoral deep venous thrombosis of pregnancy with a strategy of thrombus removal is safe and avoids post-thrombotic morbidity. J Vasc Surg. 2014;59(2):456–464.

17. Demirtürk OS, Og˘uzkurt L, Coskun I, Gülcan Ö. Endovascular treatment and the long-term results of postpartum deep vein thrombosis in 18 patients. Diagn Interv Radiol. 2012;18(6):587–593.

18. Di Nisio M, Middeldorp S. Treatment of lower extremity superficial thrombophlebitis. JAMA. 2014;311(7):729–730.