​Challenge in managing abnormal uterine bleeding in a patient on novel oral anticoagulant therapy

Abstract

This is a case report of a 48-year-old woman who presented with heavy per vaginal bleeding to the emergency department after being commenced on direct oral anticoagulants (DOACs) for venous thromboembolism. She had significant bleeding which initially required resuscitation and stabilisation. Her symptoms were ultimately managed by changing her anticoagulation agent to therapeutic low molecular weight heparin with Clexane^© the agent of choice. This case study highlights the complexity of managing these patients as well as highlighting the need for ongoing research into DOACs in this area.

Background

Direct oral anticoagulants (DOACs) are increasingly popular safe and effective alternatives to vitamin K agonists (VKA) and low molecular weight heparin (LMWH) in the treatment of venous thromboembolism (VTE) and non-valvular atrial fibrillation. However there is increasing evidence that DOAC therapy is associated with an increased incidence of abnormal uterine bleeding (AUB) with this subgroup of patients presenting a clinical management dilemma.

Pharmacological and procedural interventions as per the National Institute for Health and Care Excellence (NICE) guidelines present competing management priorities for patients with concurrent VTE and paradoxically may carry increased risk of bleeding or VTE.¹

Case presentation

Our patient was a 48-year-old woman who presented to the emergency department (ED) with heavy menorrhagia on a background of being commenced on rivaroxaban 8 days earlier for a provoked Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT) with ultrasound and computed tomography pulmonary angiogram (CTPA) finding bilateral pulmonary emboli and left soleal vein thrombosis. She had ceased her combined contraceptive pill/oral contraceptives (COCP) at the time of the diagnosis of her emboli and advised she required alternative non-hormonal method of contraception.

She reported a 3-day history of soaking through her pads every hour and passing clots with associated shortness of breath and light-headedness. Her previous medical history included multinodular toxic goitre (due for thyroidectomy) and hypertension.

She had two previous normal vaginal deliveries and her pap smears were up to date with no abnormal results. She had no previous history of AUB or heavy menstrual bleeding (HMB). Her regular medications included carbimazole 5 mg two times per day, felodipine 5 mg/day and the COCP—recently ceased. It was not noted how long she had been on the COCP prior to developing VTE. She had a Body Mass Index (BMI) of 38.4 kg/m² with a weight of 115 kg and height of 173 cm.

She denied any active cancer, no recent surgery and no previous history or family history of DVT/PE.

Investigations

Her haemoglobin on admission was 12.8 g/L, falling to 9.7 g/L the next day. A pelvic ultrasound was performed demonstrating three uterine fibroids but otherwise within normal limits (anterior myometrium—2.5×2.3×2.3 cm, fundal—2.5×2.5×2.3 cm and right lateral myometrium—1.5×1.3×1.2 cm).

Her haemoglobin was tracked during her admission with it dropping to 6.7 g/L at its lowest.

Differential diagnosis

A diagnosis of menorrhagia secondary to DOAC therapy was made with menorrhagia secondary to fibroids also considered however unlikely given her clinical history and the timing of the onset of bleeding.

Treatment

Our patient was initially stabilised in the ED and received 1.5 g tranexamic acid (TXA) with a subsequent 1 gm given the following day as she continued to bleed. A haemotologist was consulted who advised there was a contraindication to further TXA in the context of VTE and recommended changing her DOAC to a heparin infusion. She was given a total of two units of packed red blood cells. She was also commenced on 10 mg four times per day of norethistrone (Provera) to help control the bleeding in the short term.

She underwent a hysteroscopy, dilation and curettage and NovaSure ablation with mild improvement in bleeding symptoms. She was recommenced on Rivaroxaban^© and continued on a weaning dose of norethistrone for 3 weeks. Her bleeding settled in the next 24 hours and she subsequently discharged home. Endometrial histopathogical analysis was unremarkable.

She represented to the ED 5 weeks later with ongoing heavy per vaginal bleeding and a haemoglobin of 9.3 g/L. She was again treated with TXA and a Mirena^© was inserted during her admission. Her Mirena^© was subsequently expelled 2 days later. In consultation with a haematologist, her ongoing options were discussed which included insertion of an inferior vena cava filter, hysterectomy to manage menorrhagia or changing to therapeutic LMWH for treatment of her VTE. The patient opted for the last option.

She received education regarding self-administering LMWH—Clexane^© and it was slowly uptitrated to a therapeutic dose of 100 mg daily determined by her haematologist balancing her bleeding risk and need for anticoagulation. Follow-up was planned in outpatient haematology and gynaecology clinics.

Outcome and follow-up

Our patient was discharged home with outpatient obstetric and gynaecology and Haematology follow-up planned.

Her bleeding remained well controlled on Clexane^© 100 mg with a stable haemoglobin and no further episodes of menorrhagia. Follow-up ultrasound 3 months later demonstrated no evidence of an intrauterine device (IUD) (confirming expulsion as per her clinical history previously), 3 fibroids unchanged in size compared with her previous study and a normal endometrial thickness.

Her treating haematologist felt that a total of 9 months of anticoagulation would be a suitable balance between her bleeding history and VTE management.

Discussion

The increasing use of DOAC therapy can be attributed to its ease of use with no need for regular International Normalised Ratio (INR) monitoring or daily injections. There is some literature directly or indirectly looking at the incidence and severity of AUB in patients on a DOAC. Six published articles were found in a search across all journal databases, all reporting increased bleeding in patients treated with DOACs. Patients treated with rivaroxaban had rates as high as double that of patients treated with VKA.^2–7 De Crem et al’s study looking specifically at Rivaroxaban^© further showed prolonged bleeding (27% vs 8.3%) and increased contact with doctors and/or need for medical or surgical interventions in the DOAC group compared with the VKA group, respectively (38%–41% vs 13%–25%) including increased rates of transfusion and alterations to anticoagulation therapy.²

It should be noted that the increase in AUB may be specific to Rivaroxaban^© with Apixaban^© and Dabigatran^© associated with lower rates of AUB as per analysis by Godin et al.⁸ Ferreira et al found that 5.9% for the women treated with Dabigatran^© experienced AUB compared with 9.6% of women treated with warfarin.⁹ Brekelmans et al looked at data from the AMPLIFY trial comparing bleeding events between Apixaban^© and VKA. The analysis found that although there was comparable absolute number of vaginal bleeding events between Apixaban^© and LMWH and warfarin, there was an increased relative occurrence of vaginal bleeds in Apixaban^© treated women with an OR of 3.4 (95% CI).¹⁰

Ferreria’s observational study investigated the experience of patients in a community clinic of bleeding while on DOAC therapy.³ One factor noted was that the International Society on Thrombosis and Haemostasis (ISTH) definition of clinically relevant non-major bleeding does not include HMB which is likely a factor leading to the delayed recognition of AUB as a potential risk and absence of data of its prevalence.

The management of AUB comprises of medical and surgical management options with the use of TXA and hormonal options as first line.¹ Historically, TXA has been contraindicated in women with a history of VTE given its mechanism of action and concerns of inducing further VTE. A Cochrane review looking at the use of antifibrinolytics in treating AUB was unable to comment on the risk of thromboembolic events with antifibrinolytics as there was too little data to draw statistically significant conclusions.¹¹ A systematic review in 2013 again showed that TXA treatment did not consistently increase the event rate of VTE however noting that there was statistically significant increased VTE risk in some publications.¹² Given these findings it is understandable why there is still a hesitance to use TXA as evidenced in this patients care.

Insertion of hormonal IUDs such as the Mirena^© have been found to be more effective than oral medication as a treatment for HMB as per a Cochrane review evaluating the use of the levonorgestrel–releasing intrauterine system in managing AUB.¹³ However as the case above demonstrates, in the context of HMB there is a risk it will be displaced or expelled making this an unsuitable option in the acute setting.

Bryk et al further raised the issue that AUB may be linked to increased risk of VTE recurrence postulating this secondary to poor adherence to treatment rather than a pro-thrombotic predisposition in this particular subgroup of patients. They noted in the study that approximately 73% of VTE recurrence occurred while patients were on anticoagulant therapy suggesting that irregular intake of oral anticoagulants may largely contribute to VTE recurrences and further highlighting the importance of managing adverse side effects of DOACs in order to provide effective treatment for VTE.⁴

Blood Journal published a guideline in November 2017 noting that while current treatment options are effective the risk of thrombosis is not well studied, but is likely to be low.¹⁴ They suggested acute and long-term strategies based on the available evidence providing a preliminary reference tool for clinicians.

This case study highlights the complexity of managing these patients as well as highlighting the need for ongoing research into DOACs in this area.

Learning points.

• Given the increasing use of direct oral anticoagulants (DOACs) there is likely to be an associated increase in abnormal uterine bleeding (AUB) related to anticoagulation.

• The management of AUB on DOAC therapy remains a clinical dilemma with multiple but possibly competing management options and potentially increased associated risks with conventional treatment as per the current guidelines.

• No standardised evidence-based clinical practice guidelines exists to guide treatment and management in this subgroup of patients as yet and further research is needed.