Background
Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is a form of Cushing syndrome caused by excessive ACTH production, most commonly from a pituitary corticotroph adenoma, known as Cushing disease. In this condition, chronically high cortisol levels affect nearly every organ system. One of the most clinically important complications is venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism. Compared with the general population, patients with active Cushing syndrome have a substantially higher risk of clotting, especially around the time of surgery and during the period when cortisol levels remain elevated.
Despite this recognized risk, there has been no universal standard for thromboprophylaxis, or clot-preventive treatment, in ACTH-dependent Cushing syndrome. Practices vary widely between centers and may include low-molecular-weight heparin, aspirin, or no routine prophylaxis at all. This study evaluated whether routine oral rivaroxaban could safely and effectively reduce VTE in this high-risk population.
Why clot risk is high in Cushing syndrome
Cortisol excess creates a prothrombotic state. In simple terms, the blood becomes more likely to clot because of changes in coagulation factors, platelet function, vascular health, and inflammation. Patients may also have additional risk factors such as obesity, reduced mobility, hypertension, diabetes, and recent surgery. The perioperative period adds further risk because surgery itself increases clotting tendency, and recovery often involves temporary immobility.
This means that even when Cushing syndrome is being treated, the danger does not disappear immediately. Risk may persist before diagnosis, during endocrine workup, after surgery, and in the postoperative recovery period while cortisol levels normalize.
Study aim and design
The authors retrospectively reviewed 70 adults with ACTH-dependent Cushing syndrome treated between 2012 and 2025 at a single center. Patients were divided into two eras: 29 treated before 2019, when routine rivaroxaban prophylaxis was not used, and 41 treated after 2019, when the center introduced a standard policy of oral rivaroxaban 10 mg once daily for all patients with ACTH-dependent Cushing syndrome.
The main goal was to compare the incidence of VTE before and after the introduction of routine rivaroxaban. The investigators also assessed bleeding complications, blood test stability, and completion of the prophylaxis course.
Key findings
Baseline characteristics were similar in the two groups, which makes the comparison more reliable. Cushing disease was the most common subtype in both cohorts.
In the pre-2019 group, where routine prophylaxis was not given, 4 of 29 patients developed 6 VTE events, corresponding to an incidence of 13.8%. These events occurred both before surgery and after surgery, showing that clot risk was not limited to one time point.
In the post-2019 cohort, 5 patients developed 7 VTE events before endocrine assessment and before rivaroxaban could be started. This is an important detail: the events occurred early, before the preventive strategy had a chance to take effect. Two of these patients had recurrent VTE and were already on long-term therapeutic anticoagulation, so they were not part of the prophylaxis comparison. As a result, 39 of the 41 patients proceeded with rivaroxaban prophylaxis.
After routine rivaroxaban was introduced, no new VTE events were reported in patients who received prophylaxis. No major or minor bleeding complications were observed. Hematologic measurements remained stable, and all patients completed the prescribed prophylaxis course, with a median duration of 7.9 months.
Safety of rivaroxaban
Rivaroxaban is an oral direct factor Xa inhibitor widely used for preventing and treating blood clots. Compared with injectable anticoagulants, it is easier for patients to take and may improve adherence. In this study, the 10 mg once-daily prophylactic dose was well tolerated.
The absence of bleeding complications is reassuring, especially because patients with Cushing syndrome may undergo pituitary surgery or other procedures where bleeding risk must be considered carefully. Although any anticoagulant must be used with attention to surgical timing and individual risk assessment, these findings suggest that low-dose rivaroxaban can be a practical option when used in a structured protocol.
Clinical interpretation
This study suggests that routine oral rivaroxaban prophylaxis may reduce VTE in ACTH-dependent Cushing syndrome without causing excess bleeding. The results support early initiation of prophylaxis at diagnosis, rather than waiting until the postoperative period. They also support continuation through the perioperative and postoperative phases, when clot risk remains elevated.
The study does have limitations. It was retrospective, used a single-center design, and involved a relatively small number of patients. Because treatment eras were compared over time, other changes in care could also have influenced outcomes. In addition, some VTE events in the post-2019 group occurred before rivaroxaban could be started, so the study mainly supports the benefit of timely initiation rather than proving absolute prevention from the moment of diagnosis.
Even with those limitations, the findings are clinically meaningful because ACTH-dependent Cushing syndrome is uncommon, and high-quality comparative data are limited. The study adds real-world evidence that a standardized prophylaxis protocol can be both feasible and safe.
How this may affect practice
For endocrinologists, pituitary surgeons, hematologists, and perioperative teams, the message is clear: clot prevention should be considered early in patients with ACTH-dependent Cushing syndrome. A risk-based approach is still important, but the high baseline risk in this population may justify routine prophylaxis in many cases, particularly when surgery is planned or cortisol excess remains severe.
A practical management plan may include:
- Early assessment of VTE risk at diagnosis
- Prompt initiation of prophylaxis when no contraindication exists
- Coordination with surgery to manage timing around procedures
- Monitoring for bleeding, renal function, and drug interactions
- Continuation of prophylaxis through the recovery period until the hypercoagulable state improves
Because individual bleeding and clotting risks can vary, prophylaxis decisions should still be personalized. Patients with active bleeding, severe renal impairment, or other contraindications may need alternative strategies.
Bottom line
In this cohort of adults with ACTH-dependent Cushing syndrome, VTE occurred in 13.8% of patients before routine prophylaxis was introduced. After the center adopted oral rivaroxaban 10 mg once daily as standard prophylaxis, no new VTE events were seen among patients who received it, and no bleeding complications were reported.
These results support early, routine anticoagulant prophylaxis with rivaroxaban in ACTH-dependent Cushing syndrome, especially from diagnosis through the perioperative and postoperative periods. While larger prospective studies are still needed, this work provides encouraging evidence that a simple oral strategy can help prevent a serious and sometimes life-threatening complication of Cushing syndrome.