In spite of numerous trials and studies proving the efficacy of direct oral anticoagulants (DOAC) in comparison to warfarin, there is insufficient evidence of the percentage of recurrence of thromboembolic events whilst being on a DOAC.
An 81-year-old Caucasian female presented with severe pain in the right hip following an accidental fall. She had a background history of atrial fibrillation and was on a therapeutic dose of apixaban which was 5mg twice daily for the prevention of cardio-embolic complication of atrial fibrillation.
On examination, she was alert and oriented. Her vital observations were stable with normal oxygen saturation. Her right leg was shortened and externally rotated with a limited range of movement in her right hip due to pain. Her right knee had a normal range of movement. On attempting to stand, she was unable to weight bear. Her pelvic x-ray and computerised tomography (CT) scan revealed fractures to the right and left hemipelvis with hip and sacroiliac joints intact. She had a normal chest x-ray (CXR).
The medical management of the patient was delivered by a multi-disciplinary team. Following a comprehensive geriatric assessment, a trauma and orthopaedic team review was sought and plans made to manage the pelvic fractures conservatively along with adequate analgesia.
Apixaban was continued at the pre-admission dose for her atrial fibrillation. Reconciliation of her medications was done by the medical team in liaison with the ward pharmacist. During her inpatient stay with ongoing medical and physiotherapy care, on day seven post the diagnosis of pelvic fractures, she had developed decreasing oxygen saturation, especially on exertion. A CT pulmonary angiography (CTPA) scan was done which showed multiple pulmonary emboli (PE). She was then started on the therapeutic dose of apixaban 10mg twice daily for seven days and then to continue with 5mg twice daily although she was already on it for her atrial fibrillation pre-admission.
Direct oral anticoagulants (DOACs) are prescribed to reduce cardioembolic complications of atrial fibrillation and are also for secondary prevention of venous thromboembolism in the setting of a first idiopathic episode of venous thrombosis. The commonly used DOACs include apixaban, rivaroxaban, edoxaban and dabigatran. Prior to prescribing these anticoagulants, patients are normally counselled for all the risks and benefits of each of the treatment options along with their side-effects. The risk stratification scores such as HAS-BLED for risk of bleeding, and CHA2DS2-VASc for risk of stroke help to inform the choice of drug and the management strategy.
Over recent years, the use of warfarin for treatment and prevention of atrial fibrillation-associated stroke, venous thromboembolism has declined due to the increasing use of DOACs.1
This is due to the mechanism and process of pharmacokinetics, exclusion of routine monitoring of the levels of INR, fewer drug interactions and side effects of the DOAC.2 Some of the available evidence from the literature evidence suggested that apixaban is superior to warfarin in preventing systemic embolism or stroke, caused less bleeding and resulted in lower mortality as well.3 In addition to that, several studies have been conducted that compared warfarin with all the DOACs including dabigatran, edoxaban, rivaroxaban and apixaban and have concluded that DOACs have been non-inferior to the standard therapy of warfarin.
A randomised Botticelli trial was carried out on 520 patients with symptomatic embolism that showed that apixaban in all the three doses had an efficacy and safety profile that was similar to heparin.4
In addition, the AMPLIFY study conducted in 5385 patients showed that apixaban was associated with a reduction in major bleeding events. The AMPLIFY-EXT study, which was based on one-year extended anticoagulation with apixaban showed a lowered risk of recurrence in venous thromboembolism without increasing the risk of major bleeding.5
In 2013, the ARISTOTLE study was carried out to determine the superiority of apixaban compared to warfarin for the combined end-point of systemic embolism and stroke. The primary outcome of the study was that apixaban had a lower rate of systemic embolism and stroke compared to warfarin. (Hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66 to 0.95, p=0.01). It also showed that rates of pulmonary embolism, deep vein thrombosis and myocardial infarction were also lower with apixaban as compared to warfarin.6
In spite of numerous trials and studies proving the efficacy of the DOAC in comparison to warfarin, there is insufficient evidence of the percentage of recurrence of thromboembolic events, both venous and arterial, in a person who is anticoagulated on DOAC. Whilst on adequate anticoagulation, the risk of recurrence of thromboembolic events cannot be ignored. Also, it is important to rule out drug interactions with the DOAC, which might lead to decreased efficacy of the DOAC and thereby leading to a recurrence in the thromboembolic events.
There have been some reported cases of recurrence of thromboembolic events while being on DOAC as follows:
- Recurrence of PE in a 71 years old patient on rivaroxaban for known PE and concurrent carbamazepine for breast carcinoma.7
- A 64-year-old female with recurrent pulmonary embolism and a 70-year-old female with recurrent deep vein thrombosis (DVT). Both these patients were on rivaroxaban at the time of the thromboembolic recurrence.8
- The occurrence of DVT in an 80-year-old male in spite of being on apixaban treatment dose for AF.9]
Although the above cases have been highlighted the recurrence of cardio thromboembolic events, DOACs have no clear evidence in reducing the risk of cardio thromboembolic complications of atrial fibrillation in hyper coagulant states, for example, malignant conditions.
In addition to the above-mentioned cases, we and other colleague clinicians have observed similar thrombo-embolic events i.e. PE, stroke, and DVT on patients who were appropriately anticoagulated by DOAC. In some cases, the representatives from the pharmaceutical companies were also notified by us, however, they did not seem to have clear data in this context. In our case, the patient was felt to be highly compliant with her medication i.e. she had a dosette box and the medications were administered by her carers. She was not taking any other drugs causing interaction and diminished therapeutic effect of apixaban.
- There is always a risk of thromboembolic events whilst being on a DOAC.
- DOACs are not a ‘one size fits all’ solution, and patients should be carefully selected in order to maximise benefit while minimising the risk of adverse events.
- Data of thromboembolic events DOAC have not been statistically reported. Therefore, reporting of the adverse effects of DOAC should be encouraged to the MHRA Yellow Card Scheme.
- Further research and outcome-based evidence into the occurrence of thromboembolism despite patients being on DOACs should be encouraged.
S Siddique, Senior House Officer, Good Hope Hospital, Sutton Coldfield
K Singh, Consultant Geriatrician, Good Hope Hospital, Sutton Coldfield
S Potturu, Consultant Geriatrician, Good Hope Hospital, Sutton Coldfield
N Rattu, Locum Consultant Geriatrician, Good Hope Hospital, Sutton Coldfield
- Oktay E. Will NOACs become the new standard of care in anticoagulation therapy? International Journal of the Cardiovascular Academy 1 (2015) 1–4
- Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis 2015; 7: 165-7
- NICE (2013), Apixaban for preventing stroke and systemic embolism in people with atrial fibrillation. [Online] Available at: https://www.nice.org.uk/guidance/ta275
- Buller H, Deitchman D, Prins M, et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6(8): 1313-8 doi: 10.1111/j.1538-7836.2008.03054
- Franchini M, Mannucci PM. (2016) Direct Oral anticoagulants and venous thromboembolism. European Respiratory Review 2016; 25: 295-302 doi:10.1183/16000617.0025-2016
- NICE (2013). Apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation. [Online] Available at: https://www.nice.org.uk/guidance/TA275/documents/stroke-and-systemic-embolism-prevention-nonvalvular-atrial-fibrillation-apixaban-final-appraisal-determination-document2
- Burden T, Thompson C, Bonanos E, Medford AR. Lesson of the month 2: Pulmonary embolism in a patient on rivaroxaban and concurrent carbamazepine.Clin Med (Lond). 2018; 18(1): 103-105 doi: 10.7861/clinmedicine.18-1-103.
- Theodorou JM, Patel Y, Ford P. Recurrent Venous Thromboembolism in Two Patients With Cancer Taking Rivaroxaban. J Pharm Pract. 2017 Jun;30(3):381-384
- Sharma M, Ramanathan S, Khalighi K. (2017) Development of New Deep Venous Thrombosis while on apixaban. Hindawi Case Reports in Cardiology Vol 2017, Article ID 2842935