Figure. Quality improvement methodology evaluating a practice change from injectable to oral anticoagulation for extended duration venous thromevent (VTE) prophylaxis conducted at MD Anderson Cancer Center from August 2020 until September 2021. The aim was to improve patient compliance and test noninferiority (safety) of an oral direct oral anticoagulant compared to enoxaparin. The baseline data collection was set at 6 months using a noninferiority sample size estimate of n=290 (145/group) to ensure adequate data to assess safety. The intervention (apixaban) data collection was at least n=145 with an option to stop at 6 months for futility. On final analysis apixaban not only met the prespecified noninferiority threshold, but also demonstrated superiority regarding major complication incidence. In addition, there were significantly fewer compliance-related events in the apixaban group. Based on these findings, the practice change to oral direct oral anticoagulants was made permanent. Reprinted with permission from Westerman ME, J Urol. 2022;208(4):886-895.¹³

Postoperative venous thromboembolic events (VTE) are the number 1 cause of death among individuals undergoing oncologic surgery. Cancer and major abdominal surgery are both independent risk factors for the development of VTEs; an individual undergoing surgery for oncologic indications will have a 5-7 times greater risk of VTE than an individual undergoing surgery for nononcologic indications. Numerous randomized control trials, summarized in a 2019 Cochrane review, have shown a significant benefit to utilizing 28 days of low-molecular-weight heparin (LMWH) for extended duration VTE prophylaxis (EP) after major abdominal/pelvic surgery.¹ Multiple organizations, therefore, recommend EP with LMWH for up to 4 weeks postoperatively for patients undergoing open or laparoscopic abdominal or pelvic surgery for cancer.

Between 3% and 11% of patients undergoing radical cystectomy (RC) for bladder cancer develop a VTE, more than 50% of which occur after hospital discharge.² This is not just a product of historical or retrospective data. In the Intracorporeal Robotic vs Open Cystectomy trial, a randomized control trial published in 2022, 5% of patients experienced a VTE despite the use of EP.³ Although there are no randomized trials specifically evaluating the benefits of EP use after RC, previous oncologic surgery trials and retrospective RC series consistently demonstrate lower rates of VTE with no associated increase in bleeding events. For example, 1 month of LMWH after RC has been associated with a 3-fold reduction in the rate of VTE (6% no EP vs 2% EP).^2,4

Currently, the AUA strongly recommends perioperative pharmacologic VTE prophylaxis and states treatment up to 4 weeks may be beneficial.⁵ The European Association of Urology guidelines are more specific and note that the risk of VTE is essentially unchanged during the first 4 weeks after surgery, and therefore 4 weeks is the optimal duration of pharmacologic prophylaxis, thus recommending EP for all patients undergoing RC, regardless of open or robotic surgical approach.⁶

Enoxaparin, an injectable LMWH, is the most common agent used for EP. However, there are numerous barriers to using LMWH including cost, insurance coverage, need for self-injection, and side effects such as pain, bruising, and nausea. A 2020 survey of urologic oncologists by Dall et al found that nearly 40% reported barriers to LMWH use, typically cost and patient compliance.⁷

Direct oral anticoagulants (DOACs), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban), are emerging as a potential alternative to injectable LMWH. Among cancer patients, DOACs have been associated with lower rates of VTE recurrence and comparable rates of major bleeding relative to LMWH, with apixaban 2.5 mg twice daily commonly being used. Importantly, andexanet alfa (Adnexxa) was approved by the Food and Drug Administration in 2018 as the first and only antidote for anticoagulation reversal in patients treated with apixaban (and rivaroxaban).

Four recent retrospective studies, summarized in the Table, demonstrated the feasibility of using DOACs for EP after RC with no evidence of increased bleeding.^8-11 A 2020 randomized control trial comparing 28 days of apixaban or enoxaparin for the prevention of VTE following gynecologic oncology procedures also found no difference in bleeding or VTE events between groups.¹² Unsurprisingly, patients in the apixaban group reported significantly higher patient satisfaction with regard to ease of taking the medication (98.6% in the apixaban group vs 58.8% in the enoxaparin group, P < .001).¹²

Table. Summary of Recent Literature Reporting on Use of Direct Oral Anticoagulants for Extended Duration Venous Thromboembolic Event Prophylaxis After Radical Cystectomy

A 2021 prospective quality improvement study at MD Anderson Cancer Center evaluated a uniform practice change from enoxaparin to apixaban (see Figure).¹³ One hundred sixty-one patients in the enoxaparin group were compared to 154 patients in the apixaban group. Overall major complications (major bleed or symptomatic VTE) occurred in 3.1% of the enoxaparin group compared to 0% in the apixaban group (P = .028 for superiority). Compliance events (need for medication or pharmacy change due to copays, noncompliance, etc) occurred in 33.5% of patients on enoxaparin compared to 14.3% of patients on apixaban (P = .0001). Patients receiving apixaban were more likely to have a zero-dollar copay (40.3% vs 12.4%, P < .001), likely due to the availability of manufacturer co-pay coupons, which remain widely available. Based on these results, the department has continued to use apixaban as the standard for EP.

Patients undergoing RC are at high risk for VTE in the postoperative period. Four weeks of thromboprophylaxis should be strongly considered for all patients following RC. While the AUA guidelines are less specific than the European Association of Urology guidelines on recommended duration, the rationale for a minimum of 28 days of EP use is strong: bleeding risk decreases while VTE risk is constant over the first 4 weeks. In addition, apixaban is noninferior to enoxaparin for EP after urologic oncology surgery and in fact may have a more favorable safety profile, although superiority should be tested in a randomized control trial. Oral apixaban is safe, preferred by patients, and should be offered as an option for EP in bladder cancer patients following RC.