Case study: a delicate balance

Balancing anticoagulation with bleeding risk, contraception – and life.
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How do you balance the risk of significant bleeding with the need for anticoagulation in a young patient with inherited thrombophilia – complicated by the need for contraception?
Dr Kate Burbury, a consultant haematologist at the Peter MacCallum Cancer Centre in Victoria, outlines the challenging case of Sophie.

The case
Sophie, a 24-year-old woman, sustained a proximal deep vein thrombosis (DVT) following a long-haul flight from London, while on an oestrogen-containing oral contraceptive pill (OCP) for menorrhagia.

History
Sophie was previously well, without medical comorbidities, apart from clinically significant menorrhagia since the age of 18. She commenced the OCP at age 20. There was no other bleeding history and no personal, nor family, history of thrombotic complications. Sophie has one sister aged 29. She undertakes regular exercise and is a non-smoker.
Sophie undertook a long-haul flight from London Heathrow to Melbourne. Two days after her arrival, she developed pain and slight swelling in her left leg. A leg ultrasound confirmed an extensive occlusive thrombus in the left leg femoral vein.

Treatment for deep vein thrombosis (DVT)1,2
Sophie was initially commenced on low molecular weight heparin (LMWH) and bridged to warfarin, but due to INR instability was transitioned to rivaroxaban (20 mg orally daily).3 Sophie had been on rivaroxaban for 3 months and developed significant menorrhagia, lasting up to 2 weeks, resulting in notable iron deficiency and anaemia.
I was consulted to discuss appropriate management of the DVT.

Considerations for treatment
Our key issues for discussion were:

  • whether a thrombophilia screen should be performed
  • the choice of anticoagulant therapy and schedule
  • the question of how safe it was for Sophie to continue (or initiate) hormone contraceptive therapy
  • the requirement for thromboprophylaxis, in such instances as pregnancy.

Thrombophilia screening
Routine testing for hypercoagulable disorders (inheritable thrombophilia and antiphospholipid syndrome) in unselected patients with a diagnosis of venous thromboembolism (VTE) is not warranted.4
However, it can be considered in those who have a strong family history and/or those who have a strong suspicion of hypercoagulable disorder, such as patients 40 years of age or under, those with recurrent VTE, and those with VTE in unusual vascular sites.4,5
In Sophie’s case, although DVT occurred following long-haul travel (with an additional risk factor of OCP use), she is young and the event raises the suspicion of an inherited thrombophilia such as Factor V Leiden, or prothrombin gene mutation.
Identifying an inherited disorder may have important implications for future care, for example during pregnancy and hormone contraception use. This would apply to both Sophie and her sister, neither of whom have yet considered pregnancy.
When assessed, Sophie did demonstrate heterozygosity for Factor V Leiden mutation. Given the clinical significance of her phenotype, her sister was also tested, but she did not have the mutation.

Management of DVT
Management of DVT in the setting of clinically significant bleeding is challenging. The use of any anticoagulant is associated with an increased bleeding risk and up to two thirds of women on anticoagulants experience abnormal uterine bleeding.6,7
The priority is management of the DVT, which carries a significant risk of major morbidity and mortality. Clinically significant bleeding will commonly result in interruption to the anticoagulant therapy, rendering a risk of recurrent DVT during the hiatus.

Choice of anticoagulant
Following more than 12 phase III trials involving more than 200,000 patients, the direct oral anticoagulants (DOACs), such as rivaroxaban, apixaban, and dabigatran, have been demonstrated to be well tolerated and efficacious alternatives to vitamin K antagonists (VKAs), such as warfarin, and they are all now approved for the treatment of acute DVT in many countries.3,8,9

It has been found that regarding safety, DOACs have a more favourable bleeding profile than VKAs.10,11 In one particular meta-analysis of rivaroxaban versus VKAs, that included more than that 100,000 patients with atrial fibrillation or VTE, rivaroxaban was associated with lower risks of major and fatal bleeding but it increased the risk of uterine bleeding (HR 2.13; 95% CI 1.57-2.89).11

A retrospective study also demonstrated that rivaroxaban resulted in menstruation lasting longer and more frequently led to medical and/or surgical intervention (25% vs 7.7%) than warfarin.11,12

Benefits of LMWH
There is no comparable data of DOACs to LMWH with regards to recurrent VTE or bleeding risk. However, LMWH offers a number of advantages in this setting. LMWH has an extensive track record of efficacy and tolerability across a broad spectrum of patients. It has a rapid onset, predictable bioavailability, negligible drug interactions, is not influenced by nutrition, and is principally metabolised by the renal route.13–16

The anticoagulant response (anti-Xa activity) is highly correlated with body weight, which allows us to administer a fixed dose for the majority of patients. Dosing can be adjusted for patients with extremely high or low body weight, or for patients with renal failure, or for those who have additional risk factors.7,16

For LMWH, clinically significant bleeding complications are relatively uncommon, and the anticoagulant effect can be partially reversed by protamine. The half-life and dose of the LMWH given should be considered when using protamine.17–19

DOACs have a much longer half-life than LMWH and currently only dabigatran has a TGA-registered reversal agent in Australia.8,20

In Sophie’s case she suffered clinically significant bleeding requiring medical intervention, impacting her overall quality of life. I opted to convert her to the LMWH enoxaparin (Clexane) 60 mg subcutaneous (SC) daily. Her menses improved substantially with a reduction in duration and severity.

Duration of primary therapy
After an unprovoked calf DVT, thromboprophylaxis is generally recommended for three months. After an unprovoked proximal DVT, thromboprophylaxis is suggested for three to six months.21
However, the duration of therapy should parallel the duration of risk for recurrent VTE, balanced against the risk of bleeding associated with the anticoagulant therapy.21
For Sophie, in the setting of ongoing systemic hormone administration, we may need to consider concomitant anticoagulation therapy.
In this instance, Sophie’s menstrual cycle has been manageable. After restoration of her iron stores, her haemoglobin returned to near the normal range and her overall well-being improved.
She has not required re-introduction of contraceptive hormone therapy for menstruation; however, the question was raised with regards to contraception.

Precautions of using hormone contraceptive therapy in the future
Contraception counselling for women with an inherited thrombophilia should address the risks of both VTE and unintended pregnancy.22

Women with an inherited thrombophilia should be counselled that pregnancy and the postpartum period are associated with a significantly increased VTE risk and these risks may exceed the VTE risk of the patient’s contraceptive method.23

Use of oestrogen-progestin contraceptives and inherited thrombophilias both increase the risk of VTE above baseline.24

What are the risks?
Absolute risks are difficult to determine because of the small number of events in young women, even those with risk factors for VTE. VTE affects approximately 1 in every 1,200 people in Australia, with patients over 50 years of age at increased risk.25 The incidence of VTE in women who are taking the combined oral contraceptive pill is approximately 7–10/10,000 and in pregnant or postpartum women it is approximately 20–30/10,000.26 Women of childbreaing age, not taking the combined oral contraceptive have a 4 in 10,000 women risk of developing VTE each year.26

Analysing data from two clinical trials (EINSTEIN DVT and PE) that compared the safety and efficacy of rivaroxaban vs enoxaparin or warfarin in 1,888 patients (median age, 41.3 years) with acute VTE, the annual incidence of recurrent VTE was similar with or without the use of hormonal therapy (3.7% and 4.7%, respectively), and was no different with oestrogen-containing or progestin-only agents (3.7% and 3.8%, respectively).11

Although hormonal therapy is known to increase the risk of VTE, recurrent events did not appear to be more frequent in those women on anticoagulation despite resumption of either oestrogens or progestins. However, this was measured with the additional protective effect of anticoagulant.21,27,28
As such, I would advise neither starting nor continuing oestrogen-progestin contraceptives after a previous thrombotic episode.

Women with unprovoked VTE are at a particularly high risk of recurrence, which is higher than women who experience their first VTE while using oestrogen-containing agents. If the risk of a recurrent VTE in women taking oestrogen-containing agents is high, extended anticoagulation therapy may be justified.29
Preferred alternative approaches for contraception include non-hormonal or progestin-only methods, either oral, injection or via intrauterine device.26,30
Sophie is sexually active and she also had a preference for further optimisation of her menstrual bleeding and so I recommended that Sophie discuss the relative merits of an intrauterine device with a specialist gynaecologist, and she is now using an intrauterine device for contraception.

Proposed treatment strategy
Given the proximity and the extent of the thrombus, I decided to continue Sophie on enoxaparin (Clexane) 60 mg SC daily for a minimum of 6 months to complete her primary therapy for DVT. If she does not require further contraceptive hormone therapy, we will consider cessation at that time, but with meticulous secondary thromboprophylaxis in future high-risk circumstances, such as pregnancy.

Follow-up
Sophie and I will have regular, three-monthly consultations with a particular focus on:

  • weighing up the ongoing risk:benefit ratio for continuing anticoagulant therapy
  • secondary thromboprophylaxis in any future high-risk situations – in particular pregnancy, hospitalisation, surgical procedures or further long-haul travel
  • appropriate consultative advice for hormone contraception in the future.

Dr Kate Burbury is a consultant haematologist and disease group lead: myeloproliferative disorders/chronic myeloid leukaemia at the Peter MacCallum Cancer Centre in Victoria.

Dr Burbury has received speaker honoria from Sanofi, Novartis and Bayer.

 

PBS information: General Benefit Antithrombotic agent. Refer to PBS schedule for full information

 

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Full Product Information is available from sanofi australia pty ltd
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Minimum Product Information
CLEXANE® and CLEXANE® FORTE (enoxaparin sodium)
INDICATIONS:
Prevention of thrombo-embolic disorders of venous origin in orthopaedic and general surgery. Prophylaxis of venous thromboembolism in medical patients bedridden due to acute illness. Prevention of thrombosis in extracorporeal circulation during haemodialysis. Treatment of established DVT. Treatment of unstable angina and non-Q-wave MI, administered with aspirin. Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) as an adjunctive to thrombolytic treatment, including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI). DOSAGE AND ADMINISTRATION Prophylaxis of Venous Thromboembolism in (a) high risk surgical patients 40mg/day SC, (b) moderate risk surgical patients 20mg/day SC Duration of Therapy: high to moderate risk prophylaxis continued 7-10 days or until risk of thromboembolism has diminished. Prolonged Thromboprophylaxis (hip replacement): 40mg/day SC for 30 days, Medical Patients: 40mg/day SC for 6-14 days. Haemodialysis: 0.5-1mg/kg into arterial line at session start (depending on risk of haemorrhage and vascular access), add 0.5-1mg/kg if needed. Treatment of DVT: 1.5mg/kg/day or 1mg/kg/twice daily SC add warfarin within 72 hrs, when appropriate. Unstable angina and non-Q-wave MI: 1mg/kg/12 hrs SC with oral aspirin, for 2-8 days. STEMI: administered in conjunction with a fibrinolytic; patients <75yrs a 30mg single IV bolus followed by 1mg/kg/12 hours SC (maximum 100mg for each of the first 2 SC doses only), patients >75yrs 0.75mg/kg/12 hrs SC (maximum 75mg for each of the first 2 SC doses only), for 8 days or until hospital discharge. Patients undergoing PCI: If last SC dose >8hrs before balloon inflation IV bolus of 0.3mg/kg should be administered. For IV injection, use graduated prefilled syringes, administer through an IV line and do not co-administer with other medications. Dose adjustment is required in patients with severe renal impairment (CrCl<30mL/min). CONTRAINDICATIONS Allergy to Clexane, heparin or its derivatives; acute bacterial endocarditis; high risk of uncontrolled haemorrhage, including major bleeding disorders, focal lesions, haemorrhagic stroke; active ulcerative conditions showing a tendency to haemorrhage (e.g. peptic ulcer, ulcerative colitis); thrombocytopenia. PRECAUTIONS Low molecular weight heparins are not interchangeable; do not administer IM. Use with care in the following conditions - haemorrhage (bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors); pregnancy; lactation; paediatrics; elderly (increased risk of bleeding complications at therapeutic doses possible); history of heparin-induced thrombocytopenia; gastrointestinal ulceration; hepatic insufficiency; bleeding diathesis; uncontrolled arterial hypertension; impaired haemostasis; recent neuro- or ophthalmologic surgery or ischaemic stroke; recent (12-24 hours) spinal/epidural anaesthesia; diabetic retinopathy; renal impairment; low weight; obese patients (risk of thromboembolism); transmural MI being treated by thrombolytics; other agents affecting haemostasis;  prosthetic heart valves; percutaneous coronary revascularisation procedures. ADVERSE REACTIONS Haemorrhage including potentially fatal retroperitoneal or intracranial haemorrhage; wound haematoma, epistaxis, gastrointestinal haemorrhage; anaemia; thrombocytopenia; thrombocytosis; nausea; diarrhoea; peripheral oedema; fever; confusion; allergic reaction; urticaria; pruritus; erythema; increased liver enzymes; neuroaxial haematoma after spinal/epidural anaesthesia or post operative indwelling catheter; injection site reactions (including haematoma, pain, inflammation, skin necrosis); osteopenia; hyperlipidaemia; hyperkalaemia. Date of Preparation: 17 January 2017. Based on Full PI with TGA date of approval of 12 February 1993 with most recent amendment on 13 January 2017.

References: 1. Kearon C, et al. Antithrombotic therapy for VTE disease: CHEST guidelines and expert panel report. CHEST 2016; 149(2) :315-352. 2. Cleveland Clinic. Venous thromboembolism (deep vein thrombosis & pulmonary embolism), 2012. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous-thromboembolism/ (accessed 25 August 2017). 3. XARELTO (rivaroxaban) Product Information, 23 December 2016. 4. Baglin T et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149(2): 209–20. 5. Nakashima MO. and Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res 2014; 49:85-94. 6. Huq F.Y et al. Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation. Contraception 2011;84(2):128-32. 7. Queensland Health 2016. Guidelines for anticoagulation and prophylaxis using low molecular weight heparin. Ver 4, Document Number # QH-GDL-951:2015. Available from https://www.health.qld.gov.au/__data/assets/pdf_file/0023/147533/qh-gdl-951.pdf (accessed 25 August 2017). 8. PRADAXA (dabigatran) Product Information, 11 October 2016. 9. ELIQUIS (apixaban) Product Information, 3 November 2016. 10. Ruff C, Giugliano R, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet December 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0 11. Martinelli I et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016; 127(11): 1417–25. 12. De Crem N, Peerlinck K, Vanassche T et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thrombosis Research 2015. 136(4) 749-753 http://dx.doi.org/10.1016/j.thromres.2015.07.030  13. Alquwaizani M, Buckley L, Adams C et al. Anticoagulants: A review of the pharmacology, dosing and complications. Curr Emerg Hosp Med Rep 2013;1:83–97. 14. Ho W, Hankey G, Lee C et al. Venous thromboembolism:diagnosis and management of deep vein thrombosis. MJA 2005; 182: 476–481 15. Paolo Prandoni (2015) The treatment of cancer-associated venous thromboembolism in the era of the novel oral anticoagulants, Expert Opinion on Pharmacotherapy, 16:16, 2391-2394, DOI: http://dx.doi.org/10.1517/14656566.2015.1088003 16. Hirch J, Warkentin T, Shaughnessy S et al. Heparin and Low-Molecular-Weight Heparin: Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. CHEST 2001; 119:64S–94S. 17. Crowther MA and Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111(10) 4871-4879. 18. SALMINE (protamine sulphate) Product information, 23 June 2016. 19. CLEXANE (Enoxaparin sodium) Product information, 13 January 2017. 20. Strieff M, Agnelli G, Connors J et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis 2016; 41:32–67. 21. Baglin T, Bauer K, Douketis J et al. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10(4): 698–702. 22. van Vijmen et E, Veeger N, Middeldorp S et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 2011;118(8):2055-2061. 23. Batinelli E, Marshall A, & Connors J. The role of thrombophilia in pregnancy. Thrombosis 2013; Article ID 516420, 9 pages http://dx.doi.org/10.1155/2013/516420. 24. Previtali E, Bucciarelli P, Passamonti S et al. Risk factors for venous and arterial thrombosis. Blood Transfus 2011;9:120-38 DOI 10.2450/2010.0066-10. 25. Ho W, Hankey G & Eikelboom J. The incidence of venous thromboembolism: a prospective, community based study in Perth, Western Australia. Med J Aust 2008; 189:144–7. 26. Bateson D, Butcher B, Donovan C et al. Risk of venous thromboembolism in women taking the combined oral contraceptive: A systematic review and meta-analysis. Australian Family Physician 2016; 45 (1-2):59-64. 27. Prandoni P. Anticoagulant treatment of pulmonary embolism: impact and implications of the EINSTEIN PE study. Eur J Haematol 2012; 89(4): 281–7. 28. Nunnelee JD. Review of an article: oral rivaroxaban for symptomatic venous thromboembolism. The EINSTEIN Investigators et al. N Engl J Med 2010; 363(26):2499-2510. J Vasc Nurs 2011; 29(2): 89. 29. Eischer L, Eichinger S & Kyrle PA. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemostasis 2014; 12: 635-40. 30. Stam-slob M, Lambalk C & van der Ree M. Contraceptive and hormonal treatment options for women with history of venous thromboembolis. BMJ 2015; 351:h847.

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SAANZ.ENO.17.07.0228. Date of Preparation: September 2017.

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