Ultrasound-Guided Fine-Needle Aspiration Biopsy of Thyroid Nodules in Patients Taking Novel Oral Anticoagulants

Introduction

Thyroid nodules are common, with an estimated prevalence of 5.3% in women and 0.8% in men (1,2). Studies show a prevalence of 4% in the general population when utilizing palpation as the method of detection (1,3), while another study indicates that thyroid nodules are present in approximately 67% of the population when assessing by high-resolution ultrasound (1,4). Ultrasound-guided fine-needle aspiration biopsy (USGFNAB) is an accurate method of formal evaluation of a thyroid incidentaloma or suspected metastases (1), and has reduced the need for thyroid resections to distinguish benign from malignant nodules (5).

Many patients referred for USGFNAB are taking antithrombotic or anticoagulant medications, and this poses a potential concern. Antithrombotic agents such as aspirin and clopidogrel are often used as prophylaxis for coronary and cerebral vascular disease, and anticoagulant medications such as heparin and warfarin are utilized for stroke prevention in atrial fibrillation and venous thromboembolism prophylaxis. Discontinuation of these medications prior to invasive procedures does increase the potential risk of thrombotic events, but it is also important to consider the iatrogenic bleeding risks. Current recommendations and guidelines suggest stopping aspirin 10 days prior and clopidogrel seven days prior to a surgical procedure (6).

Abu-Yousef et al. (7) evaluated bleeding risks associated with USGFNAB in patients on antithrombotic/anticoagulant medications through a retrospective study of 593 patients who underwent USGFNAB of neck lesions. No patient in this study developed major bleeding complications associated with the procedure, and the study concluded that there was no statistically significant difference in the development of hematoma following USGFNAB of a neck mass in patients on antithrombotic/anticoagulant medications compared with patients not on such agents (7). Therefore, current recommendations are to decrease the risk of thromboembolic complications by avoiding preprocedural interruption of anticoagulant/antithrombotic agents prior to USGFNAB due to the low bleeding risk and incidence of hematoma (7).

Review

The novel oral anticoagulants (NOACs), including dabigatran, rivaroxaban, and apixaban, have recently been introduced for the treatment of nonvalvular atrial fibrillation and venous thromboembolism prophylaxis. There have been no studies regarding iatrogenic bleeding risks or incidence of hematomas in patients on NOACs who undergo USGFNAB for thyroid nodules. This review addresses the issue of safety of USGFNAB in patients taking NOACs, and offers recommendations for continuation of medications prior to procedures (Table 1).

Dabigatran

Dabigatran (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) reversibly inhibits direct thrombin (factor II), which converts fibrinogen to fibrin for thrombosis formation and activates platelets. Unlike heparin, dabigatran blocks free thrombin and fibrin-bound thrombin. It is 80% renally excreted. Therefore, dose adjustment is necessary for patients with renal impairment. Dabigatran has been approved for stroke prevention for nonvalvular atrial fibrillation in the United States and for venous thrombosis following orthopedic surgery in other countries. Dabigatran reaches peak activity within 2–3 h, and has a half-life of approximately 12–14 h (8,9).

There is no reversal agent for dabigatran, and there is evidence for increased bleeding in patients older than 75 years of age (10). In the Re-LY study, there was more gastrointestinal bleeding and less intracranial hemorrhage in the dabigatran group compared to warfarin (11). When determining interruption of medication prior to a surgical procedure, it is important to consider the patient's renal function, the elimination half-life of dabigatran, and the bleeding risk associated with the surgical procedure that will be performed. Current guidelines recommend that dabigatran be discontinued three days prior to elective surgery when the creatinine clearance is >50 mL/min. In a low bleeding risk procedure, taking the last dose of dabigatran two days prior to surgery may be appropriate. However, high bleeding risk surgeries would require a period of interruption to correspond with four to five half-lives of dabigatran (12,13). In patients with moderate or severe renal impairment corresponding to a creatinine clearance of <50 mL/min, the last dose of dabigatran should always be three days prior to a low bleeding risk surgery and four to five days prior to a high bleeding risk surgery. Because there still remains uncertainty regarding dabigatran discontinuation prior to surgery, it is safe to give the last dose uniformly three days prior to surgery in all patients with creatinine clearance >50 mL/min and having patients with creatinine clearance <50 mL/min essentially skip eight doses by taking the last dose of dabigatran five days prior to surgery, despite the bleeding risk of the surgical procedure (13). For the 150 mg dose twice daily, postoperative resumption of dabigatran is recommended 24 h post low bleeding risk procedure and 48 h post high bleeding risk procedure (13).

There have been no formal studies of patients on dabigatran who undergo USGFNAB for neck lesions. In patients having minor procedures or coronary angiography, it is safe to continue warfarin (13,14). Therefore, continuing dabigatran in a patient who is to undergo USGFNAB of a thyroid nodule could be considered appropriate management at this time, but further clinical correlation is needed.

Rivaroxaban

Rivaroxaban (Xarelto Janssen Pharmaceuticals, Titusville, NJ) is a direct anti-factor Xa agent, effectively blocking hemostasis by preventing the formation of thrombin. It has been approved in Europe and North America for nonvalvular atrial fibrillation and venous thromboembolism prophylaxis. Rivaroxaban reaches its maximal effect in approximately 3 h with a half-life of 5–9 h.

The ROCKET-AF (Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) was a study designed to compare once daily 20 mg rivaroxaban to dose-adjusted warfarin in the prevention of stroke in a sample of more than 14,000 patients with nonvalvular atrial fibrillation (15). This randomized trial concluded that rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation. There were no significant differences in the rates of major bleeding complications between rivaroxaban and warfarin, but intracranial and fatal bleeding did occur more frequently in the warfarin group (15). Recommendations for periprocedural interruption of rivaroxaban again focus on renal impairment. In patients with a creatinine level >50 mL/min, patients should take their last dose two days prior to surgery in low-risk surgical procedures and three days prior in high-risk procedures (13). In those patients with a creatinine level <50 mL/min, rivaroxaban should be discontinued three days prior to surgery for minor bleeding risk procedures and four days prior for high-risk bleeding procedures.

There have been no studies of bleeding risks in USGFNAB of thyroid nodules in patients on rivaroxaban, but the bleeding risks correlate with those of dabigatran. Patients should continue rivaroxaban if they are undergoing this procedure.

Apixaban

Apixaban (Eliquis Pfizer and Bristol Myers Squibb, New York, NY) is also a factor Xa inhibitor, similar in mechanism of action to rivaroxaban. It has been approved in Europe and North American for venous thromboembolism prophylaxis in orthopedic patients (12). The ARISTOTLE trial was a randomized trial that compared the efficacy of apixaban with warfarin in stroke prevention for nonvalvular atrial fibrillation. The study concluded that the apixaban group had fewer strokes and embolic events as well as less frequent major bleeding complications (16). Apixaban reaches its highest level in approximately 3–4 h, and the half-life is 10–14 h.

Recommendations for periprocedural discontinuation of apixaban are the same as for rivaroxaban, and take into consideration the patient's renal function. Similar to dabigatran and rivaroxaban, there is no proposed need for periprocedural interruption of apixaban in patients undergoing minor procedures such as an USGFNAB of a neck lesion or thyroid nodule.

Summary

Thyroid nodules are extremely common, and USGFNAB of these nodules serve as a reliable and effective means for definitive evaluation. It is also common for patients being evaluated for thyroid nodules to have comorbidities requiring chronic anticoagulation. Abu-Yousef et al. performed a retrospective study to evaluate the presence of increased bleeding risks or hematoma formation in those patients on antithrombotics or anticoagulant agents who underwent USGFNAB of neck lesions. They concluded that there was no significant bleeding risk or hematoma formation among those taking antithrombotic/anticoagulant agents compared to those who were not on these medications (7).

With the emergence of the novel oral anticoagulants (NOACs) and increase in their prevalence in clinical practice, it is important to consider the proper periprocedural management of these new anticoagulant agents. It is important to note that some of the benefits of the NOACs include their rapid onset of action and short half-life, which makes them more predictable and easy to manage prior to surgical or invasive procedures. Guidelines have been established for the interruption timing and resumption of NOACs prior to low and high bleeding risk surgical procedures, but there are no previous studies regarding patients on NOACs who undergo USGFNAB of thyroid nodules. It has also been previously established that patients on warfarin with a stable INR can undergo minor procedures such as dental procedures or needle aspirations of neck lesions without skipping any doses of warfarin (7,13). Therefore, in patients having minor procedures including USGFNAB of thyroid nodules, it is reasonable to continue dabigatran, rivaroxaban, and apixaban without risk of major bleeding complications. Further retrospective studies are needed to provide clinical data of bleeding complications and the incidence of hematomas.

Conclusion

Patients taking NOACs for stroke prevention in nonvalvular atrial fibrillation and venous thrombosis prophylaxis do not need to interrupt their anticoagulant therapy prior to or following an USGFNAB of thyroid nodules. This conclusion is based on the fact that minor procedures are considered safe for patients on NOACs and because patients on historical anticoagulants do not need to discontinue therapy prior to minor procedures such as needle aspirations. However, it is important for the proceduralist to use caution during the procedure. Patients and their guardians should be educated properly regarding the warning signs of bleeding following the procedure until further retrospective data regarding the use of NOACs and USGFNAB of thyroid nodules are available.